Phase III Double-blind, Placebo-controlled Study of AZD7442 for Pre-exposure Prophylaxis of COVID-19 in Adult.

COVID-19 Clinical Trial

— PROVENT  

Official title:

A Phase III Randomized, Double-blind, Placebo-controlled, Multi-center Study in Adults to Determine the Safety and Efficacy of AZD7442, a Combination Product of Two Monoclonal Antibodies (AZD8895 and AZD1061), for Pre-exposure Prophylaxis of COVID-19.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04625725
• Other study ID #: D8850C00002
• Secondary ID: 2020-004356-16
• Status: Completed
• Phase: Phase 3
• Start date: November 21, 2020
• Est. completion date: December 8, 2023

Study information

• Verified date: March 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will assess the safety and efficacy of a single dose of AZD7442(× 2 IM injections) compared to placebo for the prevention of COVID-19.

Description:

SARS-CoV-2 is the causative agent of the ongoing COVID-19 pandemic that, as of 29 September 2020, has resulted in a high death toll to date. Unlike the majority of coronaviruses that cause mild disease in humans and animals, SARS-CoV-2 can replicate in the lower respiratory tract to cause acute respiratory distress syndrome and fatal pneumonia. Effective interventions to prevent or treat COVID-19 remain limited in number and clinical experience is limited. Clinical management is limited to supportive care, consequently overwhelming resources of healthcare systems around the world. As a response to the ongoing pandemic, AstraZeneca is developing mAbs to the SARS-CoV-2 S protein. The SARS-CoV-2 spike protein contains the virus's RBD, which enables the virus to bind to receptors on human cells. By targeting this region of the virus's spike protein, antibodies can block the virus's attachment to human cells, and, therefore, is expected to block infection. Amino acid substitutions have been introduced into the antibodies to both extend their half-lives, which should prolong their potential prophylactic benefit, and decrease Fc effector function in order to decrease the potential risk of antibody-dependent enhancement of disease. AZD7442, a combination of 2 of these mAbs (AZD8895 and AZD1061), is being evaluated for administration to prevent and/or treat COVID-19. There is currently one completed and 2 ongoing Phase I studies with AZD7442.

-The Provent repeat dose open-label sub-study is initiated to assess the safety, PK and immunogenicity of repeat doses of AZD7442 in participants currently enrolled in the Provent study who may benefit from repeat dose of AZD7442.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5197
• Est. completion date: December 8, 2023
• Est. primary completion date: August 16, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

Inclusion Criteria:

1. = 18 years of age at the time of signing the informed consent

2. Can benefit from passive immunization with antibodies

3. Medically stable

4. Negative result from point of care SARS-CoV-2 serology testing at screening

5. Contraceptive used by women of child bearing potential, condom used by men

6. Able to understand and comply with study requirements/procedures based on the assessment of the investigator

Sub-study Inclusion criteria which are additional to those in 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:

1. Immunocompromised and/or may be at increased risk for an inadequate immune response to a COVID-19 vaccine.

2. In the opinion of the Investigator, are at increased risk and would benefit from a repeat dose of AZD7442.

• Documented negative SARS-CoV-2 RT-PCR test collected = 3 days prior to sub-study Day 1 or a negative rapid SARS-CoV-2 antigen test at screening.

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.

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. Bleeding 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. Currently pregnant or breastfeeding.

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 enrollment of participants who lack capacity to provide their own informed consent, such subjects are excluded.

Sub-study Exclusion criteria are as follows:

1. Patient have received a COVID-19 vaccination = 14 days before sub-study Day1 or plan to receive a COVID-19 vaccination = 14 days after sub-study Day1. (Such participants can subsequently be included in the study once they have reached >14 days after their last dose of vaccine).

2. Patient 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.

Related Conditions & MeSH terms

• COVID-19

Intervention

Drug:
• AZD7442
Single dose (× 2IM injections) of 300 mg of AZD7442 on parent study Day 1. Single dose (× 2IM injections) of 300 mg of AZD7442 on sub-study Day 1. Single dose (× 2IM injections) of 300 mg of AZD7442 on sub-study Day 183. Single dose (x 2IM injections) of 600mg of AZD7442 on sub-study Day 183 and Day 366
• Placebo
Single dose (× 2IM injections) of saline placebo on parent study Day 1.

Locations

Country	Name	City	State
Belgium	Research Site	Alken
Belgium	Research Site	Bruxelles
Belgium	Research Site	Gozée
Belgium	Research Site	Namur
Belgium	Research Site	Wetteren
France	Research Site	Clermont-Ferrand cedex
France	Research Site	Dijon cedex
France	Research Site	La Roche S/ Yon Cedex 9
France	Research Site	Lille
France	Research Site	Limoges cedex
France	Research Site	Nantes Cedex 1
France	Research Site	Paris cedex 10
France	Research Site	Paris cedex 14
France	Research Site	Saint Etienne Cedex 2
France	Research Site	Tours cedex 9
Spain	Research Site	Barcelona
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Marbella (Málaga)
Spain	Research Site	Pozuelo de Alarcón
United Kingdom	Research Site	Bournemouth
United Kingdom	Research Site	Enfield
United Kingdom	Research Site	Hayle
United Kingdom	Research Site	London
United Kingdom	Research Site	Preston
United Kingdom	Research Site	Rochdale
United Kingdom	Research Site	Salford
United Kingdom	Research Site	Torpoint
United Kingdom	Research Site	Wakefield
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Alexandria	Virginia
United States	Research Site	Atlanta	Georgia
United States	Research Site	Austin	Texas
United States	Research Site	Birmingham	Alabama
United States	Research Site	Bronx	New York
United States	Research Site	Cerritos	California
United States	Research Site	Chesapeake	Virginia
United States	Research Site	Chicago	Illinois
United States	Research Site	Clearwater	Florida
United States	Research Site	Columbus	Georgia
United States	Research Site	Columbus	Ohio
United States	Research Site	Conyers	Georgia
United States	Research Site	Coral Springs	Florida
United States	Research Site	El Paso	Texas
United States	Research Site	El Paso	Texas
United States	Research Site	Evansville	Indiana
United States	Research Site	Fresno	California
United States	Research Site	Garden Grove	California
United States	Research Site	Greensboro	North Carolina
United States	Research Site	Hartford	Connecticut
United States	Research Site	Hazel Crest	Illinois
United States	Research Site	Hollywood	Florida
United States	Research Site	Houston	Texas
United States	Research Site	Huntington Beach	California
United States	Research Site	Jamaica	New York
United States	Research Site	Lancaster	California
United States	Research Site	Las Vegas	Nevada
United States	Research Site	Lauderdale Lakes	Florida
United States	Research Site	Layton	Utah
United States	Research Site	Little Rock	Arkansas
United States	Research Site	Miami	Florida
United States	Research Site	Middlebury	Connecticut
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	Modesto	California
United States	Research Site	Noblesville	Indiana
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Omaha	Nebraska
United States	Research Site	Ormond Beach	Florida
United States	Research Site	Pompano Beach	Florida
United States	Research Site	Quincy	Illinois
United States	Research Site	Rapid City	South Dakota
United States	Research Site	Ridgewood	New York
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	Shenandoah	Texas
United States	Research Site	Sugar Land	Texas
United States	Research Site	Summerville	South Carolina
United States	Research Site	Tempe	Arizona
United States	Research Site	Victorville	California
United States	Research Site	Wesley Chapel	Florida
United States	Research Site	West Palm Beach	Florida
United States	Research Site	Westminster	California
United States	Research Site	Wichita	Kansas
United States	Research Site	Wichita	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Iqvia Pty Ltd

Countries where clinical trial is conducted

United States,  Belgium,  France,  Spain,  United Kingdom, 

References & Publications (18)

Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeno J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Ozguroglu M; PACIFIC Investigators. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. doi: 10.1056/NEJMoa1809697. Epub 2018 Sep 25. — View Citation

CDC. (Centers for Disease Control and Prevention). Coronavirus Disease 2019 (COVID-19), Symptoms of Coronavrus. https://www.cdc.gov/coronavirus/2019-ncov/symptomstesting/symptoms.html. Published 2020. Accessed 01 July 2020.

Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020 Apr;5(4):536-544. doi: 10.1038/s41564-020-0695-z. Epub 2020 Mar 2. — View Citation

Domachowske JB, Khan AA, Esser MT, Jensen K, Takas T, Villafana T, Dubovsky F, Griffin MP. Safety, Tolerability and Pharmacokinetics of MEDI8897, an Extended Half-life Single-dose Respiratory Syncytial Virus Prefusion F-targeting Monoclonal Antibody Administered as a Single Dose to Healthy Preterm Infants. Pediatr Infect Dis J. 2018 Sep;37(9):886-892. doi: 10.1097/INF.0000000000001916. — View Citation

Furer V, Rondaan C, Heijstek MW, Agmon-Levin N, van Assen S, Bijl M, Breedveld FC, D'Amelio R, Dougados M, Kapetanovic MC, van Laar JM, de Thurah A, Landewe RB, Molto A, Muller-Ladner U, Schreiber K, Smolar L, Walker J, Warnatz K, Wulffraat NM, Elkayam O. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2020 Jan;79(1):39-52. doi: 10.1136/annrheumdis-2019-215882. Epub 2019 Aug 14. — View Citation

Griffin MP, Khan AA, Esser MT, Jensen K, Takas T, Kankam MK, Villafana T, Dubovsky F. Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults. Antimicrob Agents Chemother. 2017 Feb 23;61(3):e01714-16. doi: 10.1128/AAC.01714-16. Print 2017 Mar. — View Citation

Griffin MP, Yuan Y, Takas T, Domachowske JB, Madhi SA, Manzoni P, Simoes EAF, Esser MT, Khan AA, Dubovsky F, Villafana T, DeVincenzo JP; Nirsevimab Study Group. Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. N Engl J Med. 2020 Jul 30;383(5):415-425. doi: 10.1056/NEJMoa1913556. Erratum In: N Engl J Med. 2020 Aug 13;383(7):698. — View Citation

Lamb EJ, Levey AS, Stevens PE. The Kidney Disease Improving Global Outcomes (KDIGO) guideline update for chronic kidney disease: evolution not revolution. Clin Chem. 2013 Mar;59(3):462-5. doi: 10.1373/clinchem.2012.184259. No abstract available. — View Citation

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Morand EF, Furie RA. Anifrolumab in Systemic Lupus Erythematosus. Reply. N Engl J Med. 2020 Apr 23;382(17):1666. doi: 10.1056/NEJMc2002191. No abstract available. — View Citation

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Robbie GJ, Criste R, Dall'acqua WF, Jensen K, Patel NK, Losonsky GA, Griffin MP. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother. 2013 Dec;57(12):6147-53. doi: 10.1128/AAC.01285-13. Epub 2013 Sep 30. — View Citation

Wagner A, Weinberger B. Vaccines to Prevent Infectious Diseases in the Older Population: Immunological Challenges and Future Perspectives. Front Immunol. 2020 Apr 23;11:717. doi: 10.3389/fimmu.2020.00717. eCollection 2020. — View Citation

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WHO. WHO R&D Blueprint COVID-19 Therapeutic Trial Synopsis Draft 18 February 2020. https://www.who.int/blueprint/priority-diseases/key-action/COVID19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf. Published 2020b. Accessed 25 September 2020.

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270-273. doi: 10.1038/s41586-020-2012-7. Epub 2020 Feb 3. Erratum In: Nature. 2020 Dec;588(7836):E6. — View Citation

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* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	AEs, SAEs, MAAEs, and AESIs Post Dose of IMP at Time of Primary Efficacy Analysis	To assess the safety and tolerability of a single IM dose of AZD7442 compared to placebo	165 Days
Primary	Number of Participants With First Case of SARS-CoV-2 RT-PCR-positive Symptomatic Illness	To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of COVID-19 prior to Day 183. Planned to be evaluated through Day 183, however, the number of events required for the primary endpoint was achieved 165 days after the study start date which is displayed in the primary efficacy row below. Final analysis is final data from the study based on the pre-planned 183 days of follow up for this endpoint.	165 Days for primary analysis, 183 days for final analysis
Primary	AEs, SAEs, MAAEs, and AESIs Post Dose of IMP	To assess the safety and tolerability of a single IM dose of AZD7442 compared to placebo	457 Days, Final analysis
Secondary	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.	To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of SARS-CoV-2 infection	366 days
Secondary	The Incidence of SARS-CoV-2 RT-PCR-positive Severe or Critical Symptomatic Illness Occurring After Dosing With IMP	To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of severe or critical symptomatic COVID-19	366 Days
Secondary	The Incidence of COVID-19-related Emergency Department Visits Occurring After Dosing With IMP	To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of COVID-19-related Emergency Department visits	366 days
Secondary	Serum AZD7442 Concentrations, PK Parameters if Data Permit.	To assess the pharmacokinetics of AZD7442 administered as a single dose of 300 mg IM	457 days
Secondary	Incidence of ADA to AZD7442 in Serum	To evaluate ADA responses to AZD7442 in serum	457 days

External Links

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•   SAP redacted