| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10051905 |
| E.1.2 | Term | Coronavirus infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of COVID-19 prior to Day 183
To assess the safety and tolerability of a single IM dose of AZD7442 compared to placebo. |
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| E.2.2 | Secondary objectives of the trial |
Key Secondary
To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of SARS-CoV-2 infection.
Other Secondary
- To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of severe or critical symptomatic COVID-19
- To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of COVID-19-related Emergency Department visits
- To assess the pharmacokinetics of AZD7442 administered as a single dose of 300 mg IM
-To evaluate ADA responses to AZD7442 in serum |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Clinical Study Protocol Addendum version 1.0 dated 01December 2021
Full title: A Phase III Multi-center, Open-label Sub-study in Adults to Assess the Safety, PK, and Immunogenicity of Repeat Doses of AZD7442, a Combination Product of Two Monoclonal Antibodies (AZD8895 and AZD1061) (The PROVENT Repeat Dose Sub-study)
Approximately 500 participants will be enrolled in the sub-study to receive repeat doses of
AZD7442.
Primary Objective is
-to evaluate the safety and tolerability of repeat doses of AZD7442 300 mg IM
Primary Endpoint is
The safety of AZD7442 will primarily be assessed by:
- Incidence of AEs
- Incidence of SAEs
- Incidence of MAAEs
- Incidence of AESIs
- Secondary Objectives are;
-To evaluate the pharmacokinetics of repeat doses of AZD7442 300 mg IM
-To evaluate ADA responses to repeat doses of AZD7442 300 mg IM in serum
-To determine anti-SARS-CoV-2 nAb levels in serum following repeat doses of AZD7442 300 mg IM
Secondary endpoints are;
-Serum AZD7442 concentrations following repeat dosing.PK parameters if data permit following repeat dosing
-Incidence of ADA to repeat doses of AZD7442 in serum
-Post-treatment GMTs and GMFRs from baseline values after a repeat IM dose in SARS-CoV-2 nAbs (wild-type assay or pseudo-neutralization assay) |
|
| E.3 | Principal inclusion criteria |
1. ≥ 18 years of age
2. Candidate for benefit from passive immunization with antibodies, defined as:
(a) Increased risk for inadequate response to active immunization (predicted poor responders to vaccines), defined as;Elderly, ie, ≥ 60 years old,Obese, ie, BMI ≥ 30, Congestive heart failure, Chronic obstructive pulmonary disease, Chronic kidney disease ie, GFR < 30 mL/min/1.73 m2,Chronic liver disease, Immunocompromised state from solid organ transplant, blood or bone marrow transplant, immune deficiencies, HIV, use of corticosteroids, or use of other immunosuppressive medicines, Intolerant of vaccine. Defined as previous history of severe adverse event or serious adverse event after receiving any approved vaccine.
(b) Increased risk for SARS-CoV-2 infection, defined as those whose locations or circumstances put them at appreciable risk of exposure to SARS-CoV-2 and COVID-19, based on available risk assessment at time of enrollment.
3. Medically stable defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 1 month prior to enrollment, with no acute change in condition at the time of study enrollment.
4. Negative result from point of care SARS-CoV-2 serology resting at screening.
5. Contraceptive use by men or women:(a) Male Participants: Contraception for male participants is not required, however, to avoid the transfer of any fluids, all male participants must use a condom from Day 1 and agree to continue through 365 days following administration of the IMP.(b) Female Participants:-Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal.
- Female participants of childbearing potential must use one highly effective form of birth control. Women of childbearing potential who are sexually active with a non-sterilized male partner must agree to use one highly effective method of birth control, as defined in the protocol from Day 1 through 365 days following administration of the IMP. Cessation of contraception after this point should be discussed with a responsible physician. All women of childbearing potential must have a negative urine pregnancy test result at Visit 1 and throughout the study as indicated per the SoA
6. Able to understand and comply with study requirements/procedures.
7. Signed informed consent.
Sub-study Inclusion criteria which are additional to those in the parent study are as follows;
-The participant has been randomized, dosed, and is ongoing in the PROVENT parent study and is 12 ± 2 months post first dose of blinded IMP.
-If one or more of the following apply:
a. Immunocompromised and/or may be at increased risk for an inadequate immune response to a COVID-19 vaccine, including:
•Elderly, ie, ≥ 60 years old
•Obese, ie, BMI ≥ 30
•Congestive heart failure
•Chronic lung disease
•Chronic kidney disease, ie, GFR < 30 mL/min/1.73 m2
•Chronic liver disease
•Immunocompromised state from solid organ transplant, blood or bone marrow transplant, immune deficiencies, human immunodeficiency virus, use of corticosteroids, or use of other immunosuppressive medicines
•Intolerant of vaccine. Defined as previous history of severe AE or SAE after receiving any approved vaccine.
b. In the opinion of the Investigator, are at increased risk and would benefit from a repeat dose of AZD7442 (eg, participants who have a chronic condition that increases their risk of severe COVID-19 or those who have not been vaccinated against COVID-19).
-Medically stable defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the one month prior to enrollment to the substudy. This includes conditions newly diagnosed since the participant entered the parent study.
-Documented negative SARS-CoV-2 RT-PCR test collected ≤ 3 days prior to SS-D1 or a negative rapid SARS-CoV-2 antigen test at screening. |
|
| E.4 | Principal exclusion criteria |
1 Significant infection or other acute illness, including fever > 100°F (> 37.8°C) on the day
prior to or day of randomization.
2. History of laboratory-confirmed SARS-CoV-2 infection or any positive SARS-CoV-2 result based on available data at screening or any positive SARS-CoV-2 result based on available data at screening.
3. History of infection with severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS).
4. Known history of allergy or reaction to any component of the study drug formulation.
5. Previous hypersensitivity, infusion-related reaction, or severe adverse reaction following administration of a mAb.
6. Any prior receipt of investigational or licensed vaccine or other mAb/biologic indicated for the prevention of SARS-CoV-2 or COVID-19 or expected receipt during the period of study follow-up.
7. Clinically significant bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venepuncture.
8. Any other significant disease, disorder, or finding that may significantly increase the risk to the participant because of participation in the study, affect the ability of the participant to participate in the study, or impair interpretation of the study data.
9. 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
10. For women only - currently pregnant (confirmed with positive pregnancy test) or breast feeding.
11. Blood drawn in excess of a total of 450 mL (1 unit) for any reason within 30 days prior to randomization.
12. Employees of the Sponsor involved in planning, executing, supervising, or reviewing
the AZD7442 program, clinical study site staff, or any other individuals involved with the conduct of the study, or immediate family members of such individuals.
13. In nations, states, or other jurisdictions that for legal or ethical reasons bar the enrolment of participants who lack capacity to provide their own informed consent, such subjects are excluded.
Sub-study Exclusion criteria are as follows;
1. Have received a COVID-19 vaccination ≤ 14 days before SS-D1 or plan to receive a COVID-19 vaccination ≤ 14 days after SS-D1. (Such participants can subsequently be included in the study once they have reached >14 days after their last dose of vaccine).
2. Have two or more untreated cardiac risk factors or suspected unstable cardiac disease.
3.Judgment by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post dose of IMP and prior to Day183.
For safety; AEs, SAEs, MAAEs, and AESIs post dose of IMP. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary endpoint;
-The key secondary endpoint is the incidence of participants who have a post-treatment response (negative at baseline to positive at any time post-baseline) for SARS-CoV-2 nucleocapsid antibodies.
Other Secondary endpoint;
- The incidence of SARS-CoV-2 RT-PCR-positive severe or critical symptomatic illness occurring post dose.
- The incidence of COVID-19-related Emergency Department visits occurring post dose.
-Serum AZD7442 concentrations.
-PK parameters if data permit.
-Incidence of ADA to AZD7442 in serum. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Belgium |
| France |
| United Kingdom |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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