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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04507256
Recruitment Status : Active, not recruiting
First Posted : August 11, 2020
Last Update Posted : August 17, 2021
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE August 7, 2020
First Posted Date  ICMJE August 11, 2020
Last Update Posted Date August 17, 2021
Actual Study Start Date  ICMJE August 18, 2020
Estimated Primary Completion Date October 22, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 13, 2020)
Number of participants with adverse events (AEs) and serious AEs [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 7, 2020)
Number of participants with adverse events (AEs) and serious AEs [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 13, 2020)
  • Observed maximum concentration (Cmax) (IV infusion) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Time to reach maximum concentration (Tmax) (IV infusion) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Terminal elimination half life, estimated as (ln2)/λz (t½λz) (IV infusion) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Area under the concentration curve from time zero to the time of last quantifiable concentration (AUClast) (IV infusion) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Area under the concentration time curve from time zero extrapolated to infinity (AUCinf) (IV infusion) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Volume of distribution at steady state (Vss) (IV infusion) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Volume of distribution at terminal phase (Vz) (IV infusion) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Systemic clearance (CL) (IV infusion) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Cmax (IM injection) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Tmax (IM injection) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • t½λz (IM injection) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • AUClast (IM injection) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • AUCinf (IM injection) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Extravascular systemic clearance (CL/F) (IM injection) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Bioavailability (F) (IM injection) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Extravascular terminal-phase volume of distribution (Vz/F) (IM injection) [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
  • Number and percentage of participants who are ADA positive [ Time Frame: From Day 1 up to last follow-up day (Day 361) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 7, 2020)
  • Observed maximum concentration (Cmax) (IV infusion) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    Cmax will be assessed after IV infusion of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Time to reach maximum concentration (Tmax) (IV infusion) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    Tmax will be assessed after IV infusion of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Terminal elimination half life, estimated as (ln2)/λz (t½λz) (IV infusion) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    t½λz will be assessed after IV infusion of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Area under the concentration curve from time zero to the time of last quantifiable concentration (AUClast) (IV infusion) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    AUClast will be assessed after IV infusion of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Area under the concentration time curve from time zero extrapolated to infinity (AUCinf) (IV infusion) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    AUCinf will be assessed after IV infusion of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Volume of distribution at steady state (Vss) (IV infusion) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    Vss will be assessed after IV infusion of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Volume of distribution at terminal phase (Vz) (IV infusion) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    Vz will be assessed after IV infusion of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Systemic clearance (CL) (IV infusion) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    CL will be assessed after IV infusion of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Cmax (IM injection) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    Cmax will be assessed after IM injection of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Tmax (IM injection) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    Tmax will be assessed after IM injection of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • t½λz (IM injection) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    t½λz will be assessed after IM injection of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • AUClast (IM injection) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    AUClast will be assessed after IM injection of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • AUCinf (IM injection) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    AUCinf will be assessed after IM injection of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Extravascular systemic clearance (CL/F) (IM injection) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    CL/F will be assessed after IM injection of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Bioavailability (F) (IM injection) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    F will be assessed after IM injection of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Extravascular terminal-phase volume of distribution (Vz/F) (IM injection) [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    Vz/F will be assessed after IM injection of AZD7442 using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher.
  • Number and percentage of participants who are ADA positive [ Time Frame: From Day 1 to up to last follow-up day (Day 361) ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE AZD7442 - a Potential Combination Therapy for the Prevention and Treatment of COVID-19
Official Title  ICMJE A Phase I Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of AZD7442 in Healthy Adults
Brief Summary 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

This is a Phase I, first time in human, randomised, double-blind, placebo-controlled, and dose escalation study.

The study will comprise of:

  1. A Screening Period of up to 27 days (Day -28 through Day -2);
  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
  3. 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Investigator)
Masking Description:
The study will be blinded for all placebo controlled dose groups, ie, the Principal Investigator (PI), all clinical staff involved in the clinical study, the participants, and the study monitor will remain blinded, unless safety concerns or a regulatory requirement necessitate unblinding.
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE
  • Combination Product: AZD7442
    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.
  • Other: Placebo
    Participants randomised to placebo will receive the same volume of solution as participants on active treatment.
Study Arms  ICMJE
  • Experimental: AZD7442
    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).
    Intervention: Combination Product: AZD7442
  • Placebo Comparator: Placebo
    Placebo will be administered to participants across five fixed-dose cohorts similar to the active treatment.
    Intervention: Other: Placebo
Publications * Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9:CD013825. doi: 10.1002/14651858.CD013825.pub2. Review.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 19, 2020)
60
Original Estimated Enrollment  ICMJE
 (submitted: August 7, 2020)
48
Estimated Study Completion Date  ICMJE October 22, 2021
Estimated Primary Completion Date October 22, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04507256
Other Study ID Numbers  ICMJE D8850C00001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Parexel
Investigators  ICMJE
Principal Investigator: Pablo Forte Soto, MD, MSc, PhD Parexel EPCU (London)
PRS Account AstraZeneca
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP