Clinical trial NCT04672395: A Controlled Phase 2/3 Study of Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Vaccine (SCB-2019) for the Prevention of COVID-19
Official title: A Double-blind, Randomized, Controlled, Phase 2/3 Study to Evaluate the Efficacy, Immunogenicity, and Safety of CpG 1018/Alum-Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) for the Prevention of SARS-CoV-2- Mediated COVID-19 in Participants Aged 12 Years and Older
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: COVID-19
Lead sponsor: Clover Biopharmaceuticals, Ltd
Sponsor class: INDUSTRY
Collaborators: name: Coalition for Epidemic Preparedness Innovations
name: International Vaccine Institute
First posted: 2020-12-17
Enrollment: 31454
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Each subject will receive 2 doses of their assigned treatment on Days 1 and 22. Booster dose will be given at least 4 months after the second dose (Day 1A for booster dose). The treatment will be administered IM in the deltoid region of the upper non-dominant arm
Primary purpose: PREVENTION

Brief summary: The purpose of this double-blind, randomized, controlled study is to evaluate the efficacy, immunogenicity, reactogenicity and safety of an adjuvanted recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) trimeric spike (S)-protein subunit vaccine (SCB-2019) for the prevention of SARS-CoV-2-mediated COVID-19 in Participants Aged 12 Years and Older.

Detailed description: This study will assess the efficacy against COVID-19, immunogenicity, reactogenicity, and safety of CpG 1018/Alum-adjuvated SCB-2019 vaccine. The COVID-19 pandemic has resulted in high morbidity and mortality, caused major disruption to healthcare systems, and has had significant socioeconomic impacts. Currently, only limited treatment options are available against COVID-19 and accelerated vaccine development is urgently needed. Several COVID-19 vaccines were recently authorized in some countries, but the global supply is insufficient for pandemic control. Additional safe and effective vaccines for COVID-19 prevention would have significant public health impact.

Placebo recipients will be offered two doses of SCB-2019 vaccine at defined points as part of the study.

Adults participants who received SCB-2019 vaccine, will be given a third dose of the SCB-2019 vaccine at least 4 months after the second dose to assess the safety and efficacy of a booster (third) dose.

Eligibility criteria: Inclusion Criteria:

1. Male or females ≥12 years of age, inclusive\*.
2. Participants who are willing and able to comply with study requirements, including all scheduled visits, vaccinations, laboratory tests, the electronic completion of the COVID-19 ePRO and other study procedures.
3. Healthy adult or adolescent subjects or adult or adolescent subjects with pre-existing medical conditions who are in stable condition. A stable medical condition is defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 3 months before enrollment.

   \*Note: The first 200 individuals enrolled in the Phase 2 part of the study should be healthy subjects 18 to 64 years or age without comorbidities associated with a high risk of severe COVID-19
4. Female subjects who are WOCBP are eligible to participate in the study if not pregnant, not breastfeeding, and at least 1 of the following criteria apply:

   * WOCBP must have a negative urine pregnancy test prior to each vaccination. A confirmatory serum pregnancy test may be conducted at the investigator's discretion.
   * They must be using a highly effective licensed method of birth control for 30 days prior to the first vaccination and must agree to continue such precautions during the study until 90 days after the second vaccination.
5. Male subjects must agree to employ acceptable contraception from the day of first dose of the study vaccine/placebo until 6 months after the last dose of the study vaccine/placebo and also refrain from donating sperm during this period.
6. Individuals (or their legally acceptable representative based on local regulations) willing and able to give an informed consent, prior to screening. For adolescent subjects: informed assent signed by adolescents and informed consent signed by the parent(s) or legally acceptable representative(s) as per local requirements.
7. Applicable for HIV-positive individuals only if:

They are medically stable at screening, as determined by the investigator, and free of opportunistic infections in the 1 year prior to first study vaccination, and They have an HIV-1 viral load \<1000 copies/mL within 45 days of randomization in the study, and They are receiving highly active antiretroviral therapy (HAART) for at least 3 months before screening. Changes in antiretroviral dosage within 3 months of entering the study are allowed, as are exchanges in pharmacological formulations.

Exclusion Criteria:

1. Individuals with laboratory-confirmed SARS-CoV-2 infection (e.g., a positive RT-PCR\* or Rapid COVID-19 Antigen test) at screening or within 14 days prior to enrollment.
2. Individuals with behavioral or cognitive impairment (including drug and alcohol abuse) in the opinion of the investigator.
3. Individuals with any progressive or severe neurologic disorder, seizure disorder, or history of Guillian-Barré syndrome.
4. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, e.g., for cancer or an autoimmune disease, or planned receipt during the study period.
5. Individuals who are pregnant, or breastfeeding, or planning to become pregnant during the study period.
6. Individuals who have a history of severe adverse reaction associated with a vaccine or severe allergic reaction (e.g., anaphylaxis) to any component of the study vaccine (SCB-2019, CpG1018 Adjuvant and Aluminum hydroxide components).
7. Individuals who have a history of malignancy within 1 year before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix which have been cured, or other malignancies with minimal risk of recurrence).
8. Individuals who have received any other investigational product within 30 days prior to Day 1 or intent to participate in another clinical study at any time during the conduct of this study.
9. Individuals who have received previous vaccination with any coronavirus vaccine.
10. Individuals who have received any other licensed vaccines within 14 days prior to enrollment in this study or who are planning to receive any vaccine up to 14 days after the second vaccination.
11. Individuals with known bleeding disorder that would, in the opinion of the investigator, contraindicate intramuscular injection.
12. Individuals who received any blood/plasma products or immunoglobulins within 60 days prior to Day 1 or plan to receive it during the study period.
13. Individuals with any condition that, in the opinion of the investigator, may increase the risk of study participation or interfere with the assessment of the primary study objectives.
14. Individuals with fever \>37.8°C (irrespective of method), or any acute illness at baseline (Day 1) or within 3 days of randomization.

Primary outcomes:
measure: Number of Participants with a First Occurrence of COVID-19 of Any Severity Starting 14 Days after Second Dose of SCB-2019
timeFrame: Day 36 up to Day 389 (1 year after second dose)
measure: Number of Participants with Solicited Local and Systemic Adverse Reactions (ARs)
timeFrame: Up to Day 8 (7 days after first dose) and up to Day 29 (7 days after second dose)
measure: Number of Participants with Unsolicited AEs
timeFrame: Up to Day 43 (21 days after each dose)
measure: Number of Participants with Serious Adverse Events (SAEs), or Medically Attended AEs (MAAEs), or AEs Leading to Early Termination, or Adverse Events of Special Interest (AESIs)
timeFrame: Up to Day 389 (1 year after second dose)
measure: Non-inferiority of the neutralizing titers after third dose compared to the neutralizing titers after second dose
timeFrame: 14 days after third dose
measure: Non-inferiority of the neutralising titers in adolescents versus young adults.
timeFrame: 14 days after second dose
Secondary outcomes:
measure: Number of Participants with a First Occurrence of Moderate-to-Severe COVID-19 Starting 14 Days after Second Dose of SCB-2019
timeFrame: Day 36 up to Day 389 (1 year after second dose)
measure: Number of Participants with First Occurrence of Any Laboratory-Confirmed SARS-CoV-2 infection Starting 14 Days after Second Dose of SCB-2019 or Placebo
timeFrame: Day 36 up to Day 389 (1 year after second dose)
measure: Number of Participants with a First Occurrence of Severe COVID-19 Starting 14 Days after Second Dose of SCB-2019 or Placebo
timeFrame: Day 36 up to Day 389 (1 year after second dose)
measure: Number of Participants with First Occurrence of Any Laboratory-Confirmed Asymptomatic SARS-CoV-2 infection Starting 14 Days after Second Dose of SCB-2019 or Placebo
timeFrame: Day 36 up to Day 389 (1 year after second dose)
measure: Burden of Disease Score of COVID-19 or SARS-CoV-2 Infection Cases Starting 14 Days after Second Dose of SCB-2019 or Placebo
timeFrame: Day 36 up to Day 389 (1 year after second dose)
measure: Number of Participants with a First Occurrence of COVID-19 of Any Severity, Associated with Hospitalization, Starting 14 Days after Second Dose of SCB-2019 or Placebo
timeFrame: Day 36 up to Day 389 (1 year after second dose)
measure: Number of Participants with a First Occurrence of COVID-19 Starting 14 days after Second Dose of SCB-2019 or Placebo, regardless of evidence of prior SARS-CoV-2 Infection
timeFrame: Day 36 up to Day 389 (1 year after second dose)
measure: Number of Participants with a First Occurrence of COVID-19 Starting 14 days after Second Dose of SCB-2019 or Placebo, regardless of risk of severe COVID-19
timeFrame: Day 36 up to Day 389 (1 year after second dose)
measure: Number of Participants with a First Occurrence of COVID-19 Starting 14 days after First Dose of SCB-2019 or Placebo
timeFrame: Day 15 up to Day 22
measure: Number of Participants with a First Occurrence of COVID-19 of Any Severity caused by SARS-CoV-2 variants of concern starting 14 days after Second Dose
timeFrame: Day 36 up to Day 389 (1 year after second dose)
measure: Geometric Mean Titer (GMT) of SARS-CoV-2 Specific Neutralizing Antibody (nAb)
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Geometric Mean Fold Rise (GMFR) of SARS-CoV-2 Specific nAb
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Number of Participants with Seroconversion for SARS-CoV-2 Specific nAb
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Geometric Mean Titer (GMT) of SARS-CoV-2 antibodies competing for binding of S protein to the human ACE2 receptor
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Geometric Mean Fold Rise (GMFR) of SARS-CoV-2 antibodies competing for binding of S protein to the human ACE2 receptor
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Number of Participants with Seroconversion for of SARS-CoV-2 antibodies competing for binding of S protein to the human ACE2 receptor
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Geometric Mean Titer (GMT) of SCB-2019 binding antibody
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Geometric Mean Fold Rise (GMFR) of SCB-2019 binding antibody
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Number of Participants with Seroconversion for SCB-2019 binding antibody
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Geometric Mean Titer (GMT) of Trimer-Tag binding antibody
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Geometric Mean Fold Rise (GMFR) of Trimer-Tag binding antibody
timeFrame: Day 1, Day 22, Day 35, Day 205, and Day 389
measure: Number of Participants with Solicited Local and Systemic Adverse Reactions (ARs)
timeFrame: Up to 7 days after booster dose
measure: Number of Participants with Unsolicited AEs
timeFrame: Up to 21 days after booster dose
measure: Number of Participants with Serious Adverse Events (SAEs), or Medically Attended AEs (MAAEs), or AEs Leading to Early Termination, or Adverse Events of Special Interest (AESIs)
timeFrame: Up to 6 months after booster dose
measure: Geometric Mean Titer (GMT) of SARS-CoV-2 Specific nAb
timeFrame: Day 1A, Day 15A (15 days after booster), and Day 389A (6 months after booster)
measure: Geometric Mean Fold Rise (GMFR) of SARS-CoV-2 Specific nAb
timeFrame: Day 1A, Day 15A (15 days after booster), and Day 389A (6 months after booster)
measure: Number of Participants with Seroconversion for SARS-CoV-2 Specific nAb
timeFrame: Day 1A, Day 15A (15 days after booster), and Day 389A (6 months after booster)
measure: Geometric Mean Titer (GMT) of SCB-2019 binding antibody
timeFrame: Day 1A, Day 15A (15 days after booster), and Day 389A (6 months after booster)
measure: Geometric Mean Fold Rise (GMFR) of SCB-2019 binding antibody
timeFrame: Day 1A, Day 15A (15 days after booster), and Day 389A (6 months after booster)
measure: Number of Participants with Seroconversion for SCB-2019 binding antibody
timeFrame: Day 1A, Day 15A (15 days after booster), and Day 389A (6 months after booster)
Other outcomes:
Locations:
city: Alken
country: Belgium
facility: Anima
city: Bruxelles
country: Belgium
facility: Hôspital Erasme
city: Namur
country: Belgium
facility: Private Practice RESPISOM Namur
city: Rio de Janeiro
country: Brazil
facility: Instituto D'OR de Pesquisa e Ensino
state: Rio Do Janeiro
city: Natal
country: Brazil
facility: Instituto Atena de Pesquisa Clinica
state: Rio Grande Do Norte
city: Natal
country: Brazil
facility: CPCLIN - Centro de Pesquisas Clínicas de Natal
state: Rio Grande Do Norte
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande Do Sul
city: Santa Maria
country: Brazil
facility: Hospital da Universidade Federal de Santa Maria CEP/UFSM
state: Rio Grande Do Sul
city: Acacías
country: Colombia
facility: Centro de Atención e investigación Médica S.A.S, CAIMED S.A.S - sede, Acacias
city: Aguazul
country: Colombia
facility: Centro de Atención e investigación Médica S.A.S, CAIMED S.A.S - sede Aguazul
city: Barranquilla
country: Colombia
facility: Clínica de la Costa Ltda
city: Barranquilla
country: Colombia
facility: Fundación Hospital Universitario del Norte
city: Bogotá
country: Colombia
facility: Centro de Atención e investigación Médica S.A.S, CAIMED S.A.S - sede, Bogotá D.C.
city: Bogotá
country: Colombia
facility: Policlinico Social del Norte
city: Cali
country: Colombia
facility: Centro de Estudios en Infectología Pediátrica S.A.S. - CEIP S.A.S.
city: Manizales
country: Colombia
facility: IPS Médicos Internistas de Caldas SAS
city: Yopal
country: Colombia
facility: Centro de Atención e investigación Médica S.A.S, CAIMED S.A.S - sede, Yopal
city: Dasmariñas
country: Philippines
facility: De La Salle Medical and Health Sciences Institute
state: Cavite
city: Las Piñas
country: Philippines
facility: Las Pinas Doctors Hospital
city: Makati
country: Philippines
facility: Tropical Disease Foundation
city: Manila
country: Philippines
facility: Manila Doctors Hospital
city: Muntinlupa
country: Philippines
facility: Asian Hospital and Medical Center
city: Pasay
country: Philippines
facility: University of the Philippines Manila - Philippine General Hospital
city: Quezon City
country: Philippines
facility: UERM Memorial Medical Center
city: Quezon City
country: Philippines
facility: University of the East Ramon Magsaysay Memorial Medical Center
city: Quezon City
country: Philippines
facility: FEU-NRMF Medical Center
city: Taguig
country: Philippines
facility: St. Luke's Medical Center
city: Johannesburg
country: South Africa
facility: Wits Clinical Research
state: Gauteng
city: Krugersdorp
country: South Africa
facility: DJW Research
state: Gauteng
city: Soweto
country: South Africa
facility: Soweto Clinical Trials Centre
state: Gauteng
city: Somerset West
country: South Africa
facility: Dr JM Engelbrecht Trial Site
state: Western Cape
Study officials:
affiliation: Clover Biopharmaceuticals AUS Pty
name: Igor Smolenov, MD, PhD
role: STUDY_CHAIR
References:
citation: Liu H, Su D, Zhang J, Ge S, Li Y, Wang F, Gravel M, Roulston A, Song Q, Xu W, Liang JG, Shore G, Wang X, Liang P. Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo. Sci Rep. 2017 Aug 21;7(1):8953. doi: 10.1038/s41598-017-09518-1.
citation: Ruggeberg JU, Gold MS, Bayas JM, Blum MD, Bonhoeffer J, Friedlander S, de Souza Brito G, Heininger U, Imoukhuede B, Khamesipour A, Erlewyn-Lajeunesse M, Martin S, Makela M, Nell P, Pool V, Simpson N; Brighton Collaboration Anaphylaxis Working Group. Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2007 Aug 1;25(31):5675-84. doi: 10.1016/j.vaccine.2007.02.064. Epub 2007 Mar 12. No abstract available.
citation: Rhodes SJ, Knight GM, Kirschner DE, White RG, Evans TG. Dose finding for new vaccines: The role for immunostimulation/immunodynamic modelling. J Theor Biol. 2019 Mar 21;465:51-55. doi: 10.1016/j.jtbi.2019.01.017. Epub 2019 Jan 10.
citation: Food and Drug Administration letter. Device: BinaxNOW COVID-19 Ag Card. 26 August 2020. https://www.fda.gov/media/141567/download. Accessed on 15 September 2020.
citation: Amai M, Nojima M, Yuki Y, Kiyono H, Nagamura F. A review of criteria strictness in "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials". Vaccine. 2023 Aug 31;41(38):5622-5629. doi: 10.1016/j.vaccine.2023.07.072. Epub 2023 Aug 1.
citation: Safety Platform for Emergency vACcines (SPEAC). D2.3 Priority List of Adverse Events of Special Interest: COVID-19. V1.1 Date 05 March 2020. https://media.tghn.org/articles/COVID-19_AESIs_SPEAC_V1.1_5Mar2020.pdf. Accessed on 15 September 2020.
citation: Chan ISF, Bohidar NR (1998) Exact power and sample size for vaccine efficacy studies, Communications in Statistics - Theory and Methods 1998;27(6):1305-22.
citation: Maurer W, Bretz F. Multiple testing in group sequential trials using graphical approaches. Stat Biopharm Res 2013;5(4):311-20.
citation: Bravo L, Smolenov I, Han HH, Li P, Hosain R, Rockhold F, Clemens SAC, Roa C Jr, Borja-Tabora C, Quinsaat A, Lopez P, Lopez-Medina E, Brochado L, Hernandez EA, Reynales H, Medina T, Velasquez H, Toloza LB, Rodriguez EJ, de Salazar DIM, Rodriguez CA, Sprinz E, Cerbino-Neto J, Luz KG, Schwarzbold AV, Paiva MS, Carlos J, Montellano MEB, de Los Reyes MRA, Yu CY, Alberto ER, Panaligan MM, Salvani-Bautista M, Buntinx E, Hites M, Martinot JB, Bhorat QE, Badat A, Baccarini C, Hu B, Jurgens J, Engelbrecht J, Ambrosino D, Richmond P, Siber G, Liang J, Clemens R. Efficacy of the adjuvanted subunit protein COVID-19 vaccine, SCB-2019: a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2022 Jan 29;399(10323):461-472. doi: 10.1016/S0140-6736(22)00055-1. Epub 2022 Jan 20.