| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 |
Main Cohort
1.To evaluate the safety of AZD3152 and EVUSHELD and/or placebo
2. To compare the efficacy of AZD3152 to EVUSHELD and/or placebo in the prevention of symptomatic COVID-19
caused by any SARS CoV 2
variant
3. To compare the efficacy of AZD3152 to EVUSHELD and/or placebo in
the prevention of symptomatic COVID 19 attributable to matched
variants (variants that do not contain the F456L mutation)
Sentinel Safety Cohort
1.To evaluate the safety of AZD5156 |
|
| E.2.2 | Secondary objectives of the trial |
Main Cohort
1. To compare the nAb responses to the SARS-CoV-2 variants Alpha,
Omicron BA.2, Omicron BA.4/5 and/or Omicron XBB.1.5 in serum
following AZD3152 and EVUSHELD and/or placebo administration
2.To describe the incidence of symptomatic COVID-19, severe COVID19, COVID-19 related hospitalization, and COVID-19 related death in participants receiving study intervention
3.To characterize the PK of AZD3152 and AZD7442 in serum
4.To evaluate the ADA responses to AZD3152 and AZD7442 in serum
Sentinel Safety Cohort
1.To characterize the PK of AZ5156 and AZD3152 in serum
2.To evaluate the ADA responses to AZD5156, AZD3152 and AZD1061 in serum |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Sentinel Safety Cohort Participants (Phase I)
Participants are eligible to be included in the Sentinel Safety Cohort only
if all of the following criteria apply:
1.Healthy participants according to medical history, physical
examination, baseline safety laboratory tests, and screening parameters, according to the judgment of the investigator, with no concomitant
disease or concomitant medication (except for medication specifically
permitted by the protocol)
2.Age 18 to 55 years at the time of signing the informed consent
3. Written informed consent and any locally required authorization (eg,
HIPAA in the US) obtained from the participant prior to performing any
protocol-related procedures, including screening evaluations.
4.Negative rapid antigen test at Visit 1
5.Weight ≥ 45 kg and ≤ 110 kg at screening
Main Cohort Participants (Phase III)
Participants are eligible to be included in the Main Cohort only if all of
the following criteria apply:
1.Participant must be 12 years of age or older at the time of signing the
informed consent.
2. Written informed consent and any locally required authorization (eg,
HIPAA in the US) obtained from the participant prior to performing any
protocol-related procedures, including screening evaluations. For
participants from 12 to < 18 years of age, their parents or legal
guardians must give their signed written informed consent, as
appropriate, and participants will sign an assent form.
3.Negative rapid antigen test prior to dosing at Visit 1.
4.Weight ≥ 40 kg at screening
5.Participants must satisfy at least 1 of the following risk factors at
enrollment:
•Have solid tumor cancer and be on active immunosuppressive
treatment
•Have hematologic malignancy
•Transplant participants must satisfy at least one of the following:
o Have had a solid organ transplant within 2 years and / or
o Had a hematopoietic stem cell transplant within 2 years and / or
o Who have chronic graft-versus-host disease
o Participants who previously had a solid organ transplant or
hematopoietic stem cell transplant more than 2 years prior to Visit 1 may also be eligible based on the inclusion criterion for immunosuppressive treatment
•Are actively taking immunosuppressive medicines (eg, are using
corticosteroids [ie,≥ 20 mg prednisone or equivalent per day when
administered for ≥ 2 weeks], alkylating agents, antimetabolites,
transplant-related immunosuppressive drugs, cancer chemotherapeutic
agents classified as severely immunosuppressive [eg,Bruton's tyrosine
kinase inhibitors], tumor-necrosis blockers, or other immunosuppressive
biologic agents (eg, for rheumatic diseases)
•Received chimeric antigen receptor T cell therapy
•Within 1 year of receiving B-cell depleting therapies (eg, rituximab,
ocrelizumab, ofatumumab, alemtuzumab)
•Have a moderate or severe primary (eg, DiGeorge syndrome) or
secondary (eg, hemodialysis) immunodeficiency
• Advanced or untreated HIV infection (people with HIV and CD4 cell
counts < 200/mm3 within 6 months of Visit 1, history of an AIDSdefining illness without immune reconstitution, or clinical manifestations
of symptomatic HIV)
6.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 as judged by the Investigator and no expected changes at the time of the enrollment
7 Able to understand and comply with all study requirements/procedures (if applicable, with assistance by caregiver, surrogate, or legally authorized representative or equivalent representative as locally defined), including those at Illness Visits, based on the assessment of the Investigator.
|
|
| E.4 | Principal exclusion criteria |
Sentinel Safety Cohort Participants (Phase I)
Participants are excluded from the Sentinel Safety Cohort if any of the
following criteria apply:
1.Women who are pregnant, lactating, or of childbearing potential and
not using a highly effective method of contraception or abstinence from at least 4 weeks prior to study intervention adm and until at least 6
months after study intervention adm (see details in CSP)
2.Known hypersensitivity to any component of the study intervention.
3.Previous hypersensitivity or severe adverse reaction following administration of mAb.
4.Acute (time-limited) or febrile (temperature ≥ 38.0°C illness/infection
on day prior to or day of planned dosing; participants excluded for
transient acute illness may be dosed if illness resolves within the
screening period or may be rescreened once.
5.Blood drawn in excess of a total of 450 mL (1 unit) for any reason
within 30 days prior to Visit 1.
6.Clinically significant bleeding disorder (eg, factor deficiency,
coagulopathy, or platelet disorder), or prior history of significant
bleeding or bruising following IM inj or venipuncture.
7..Receipt of IV or SC immunoglobulin within 6 months prior to Visit 1 or
expected to receive IV or SC immunoglobulin 6 months after dosing.
8.Previous receipt of a mAb against SARS-CoV-2
9.Receipt of a COVID-19 vaccine within 3 months prior to Visit 1
10.Receipt of a COVID-19 antiviral for prophylaxis within at least 2
weeks prior to Visit 1
11.COVID-19 within 3 months prior to Visit 1 (confirmed either by
laboratory testing or a rapid test [including at home testing])
12. 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.
Main Cohort Participants (Phase III)
Participants are excluded from the Main Cohort if any of the following
criteria apply:
1.Women who are pregnant, lactating, or of childbearing potential and not using a highly effective method of contraception or abstinence from at least 4 weeks prior to study intervention administration and until at least 6 months after study intervention administration. Note: female participants aged > 12 years will be considered to be a woman of childbearing potential(see details in CSP)
2.Known hypersensitivity to any component of the study intervention.
3.Previous hypersensitivity or severe adverse reaction following
administration of a mAb.
4.Acute (time-limited) or febrile (temperature ≥ 38.0°C [100.4ºF])
illness/infection on day prior to or day of planned dosing; participants
excluded for transient acute illness may be dosed if illness resolves and may be rescreened for enrollment once.
5.Blood drawn in excess of a total of 450 mL (1 unit) for any reason
within 30 days prior to Visit 1.
6.Clinically significant bleeding disorder (eg, factor deficiency,
coagulopathy, or platelet disorder), or prior history of significant
bleeding or bruising following IM injections or venipuncture.
7.Receipt of IV or SC immunoglobulin within 6 months prior to Visit 1 or expected to receive IV and SC immunoglobulin 6 months after dosing.
8 Receipt of convalescent COVID-19 plasma treatment within 6 months prior to Visit 1.
9 Previous receipt of a mAb against SARS-CoV-2 within 6 months prior to Visit 1.
10 Receipt of a COVID-19 vaccine within 3 months prior to Visit 1.
11 Receipt of a COVID-19 antiviral for prophylaxis within at least 2
weeks prior to Visit 1.
12 COVID-19 within 3 months prior to Visit 1 (confirmed either by
laboratory testing or arapid test [including at-home testing]).
13 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 (except where the participant ceased IMP treatment >90 days and is in the follow-up period of the study and not expected to receive further IMP).
14 Alcohol or substance abuse that, in the opinion of the Investigator,
might interfere with the trial conduct or completion.
15 Deprived of freedom by an administrative or court order, or in
emergency setting, or hospitalized involuntarily. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Main Cohort
1.Occurrence of AEs collected through approximately 90 days after each IMP administration; SAEs, MAAEs and AESIs collected through the study
Population: SARS-CoV-2-Negative Set
Endpoint: Confirmed symptomatic COVID-19 case, classified as a binary
outcome incorporating the time from the first dose of IMP until a
participant develops their first symptoms for COVID-19, which is defined
as:
• Positive post-baseline RT-PCR at any time up to 181 days after last
dose (ie, Visit 9 [Day 361] for participants who receive both planned
treatment administrations) AND
• Satisfying modified WHO definition of symptomatic COVID-19
Intercurrent events: Participants who become unblinded to study
intervention assignment and/or take other non-investigational
product(s) for COVID-19 prevention prior to having met the criteria for
the COVID-19 endpoint. Such participants will be censored at the earliest
of the following:
• The date of unblinding
• Receipt of the first dose of any COVID-19 preventive product
Summary measure: Prophylactic efficacy, calculated as 1-HR (AZD3152
versus EVUSHELD and/or placebo) using a hazard regression model
3. Population: SARS-CoV-2-Negative Set
Endpoint: Confirmed symptomatic COVID-19 case attributable to
matched variants, classified as a binary outcome incorporating the time
from the first dose of IMP until a participant develops their first
symptoms for COVID-19, which is defined as:
• Positive post-baseline RT-PCR at any time up to 181 days after last
dose (ie, Visit 9 [Day 361] for participants who receive both planned
treatment administrations) AND
• Satisfying the modified WHO definition of symptomatic COVID-19 AND
• Viral sequencing from associated positive RT-PCR is attributable to
matched variants
Intercurrent events: Participants who become unblinded to study
intervention assignment and/or take other non-investigational
product(s) for COVID-19 prevention prior to having met the criteria for
the COVID-19 endpoint. Additionally, RT-PCR-confirmed symptomatic
COVID-19 infections that are either unrelated to matched variants or
undetermined variants will be considered intercurrent events. Such
participants will be censored at the earliest of the following:
• The date of unblinding
• Receipt of the first dose of any COVID-19 preventive product
• Date of first occurrence of an RT-PCR-confirmed symptomatic COVID‑
19 case not attributable to a matched variant
Analysis strategy: While-on-treatment strategy –participants will be
analyzed according to randomized treatment and censored at the time of
the earliest intercurrent event prior to having met the criteria for the
endpoint.
Summary measure: Prophylactic efficacy, calculated as 1-HR (AZD3152
versus EVUSHELD and/or placebo) using a hazard regression model.
Sentinel Safety Cohort
1.Occurrence of AEs collected through approximately 90 days after IMP administration; SAEs, MAAEs, and AESIs collected through the study
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary (Main Cohort)
For safety: Occurrence of AEs collected through approximately 90 days
after IMP administration. SAEs, MAAEs, and AESIs collected throughout
the study
For Efficacy: Negative RT-PCR at baseline to positive at any time up to
Visit 9 (12 months) AND
Satisfying modified WHO definition of symptomatic COVID-19
Primary (Sentinel Safety Cohort)
For safety: Occurrence of AEs collected through approximately 90 days
after IMP administration.
SAEs, MAAEs, and AESIs collected throughout the study |
|
| E.5.2 | Secondary end point(s) |
Main Cohort
1.Geometric mean titer (GMT) and geometric mean fold rise (GMFR) ratio
of SARS-CoV-2 nAbs between the treatment arms at Visit 3 (Day 29).
2.Incidence of a post treatment:
• Symptomatic COVID-19 case (negative RT PCR at baseline to positive
at any time up to 6 and 12 months) caused by any SARS-CoV-2 variant
• Symptomatic COVID-19 case (negative RT PCR at baseline to positive
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at any time up to 6 and 12 months) caused by any SARS-CoV-2 matched
variants
•Severe COVID-19 caused by any SARS-CoV-2 variant
• Severe COVID-19 caused by any SARS-CoV-2 matched variants
•Composite of COVID-19 related hospitalization and/or COVID-19
related death
•COVID-19 related hospitalization (separately)
•COVID 19 related death (separately)
3. AZD3152, AZD7442, AZD1061 and AZD8895 concentrations over time
and PK parameters
In the Main Cohort: AZD5156, and AZD7442, AZD1061, AZD3152, and
AZD8895 concentrations over time
4.Incidence of ADA
Sentinel Safety Cohort
1.AZD5156, AZD1061, and AZD3152 concentrations over time and PK
parameters
2.Incidence of ADA |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
GMT and GMFR ratio of SARS-CoV-2 nAbs between the treatment arms at
Visit 3 (Day 29).
Descriptive statistics for GMTs and GMFRs will include the number of
participants, geometric mean, gSD, 95% CI, minimum, and maximum
and summarized by treatment arm and visit |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| 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 |
| Malaysia |
| Korea, Democratic People's Republic of |
| Taiwan |
| Canada |
| Israel |
| Thailand |
| United Kingdom |
| United States |
| Viet Nam |
| Belgium |
| Denmark |
| France |
| Germany |
| Poland |
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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