Clinical Trial Results:
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
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Summary
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EudraCT number |
2020-004272-17 |
Trial protocol |
BE DE |
Global end of trial date |
11 Sep 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Jan 2025
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First version publication date |
12 Jan 2025
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Other versions |
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Summary report(s) |
primary analysis immunogenicity 6 months follow-up |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CLO-SCB-2019-003
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Additional study identifiers
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ISRCTN number |
ISRCTN00000000 | ||
US NCT number |
NCT04672395 | ||
WHO universal trial number (UTN) |
U0000-0000-0000 | ||
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Sponsors
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Sponsor organisation name |
Clover Biopharmaceuticals AUS pty Ltd
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Sponsor organisation address |
Level 17, HWT Tower, 40 City Road, Southbank VIC, Melbourne, Australia, 3006
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Public contact |
Htay Htay Han, Clover Biopharmaceuticals AUS Pty Ltd, htayhtay.han@cloverbiopharma.com
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Scientific contact |
Htay Htay Han, Clover Biopharmaceuticals AUS Pty Ltd, htayhtay.han@cloverbiopharma.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
13 Sep 2024
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
17 Dec 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Sep 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
1. Primary Efficacy Objective: Vaccine Efficacy Against RT-PCR-Confirmed COVID-19 of Any Severity: To demonstrate the efficacy of CpG 1018/Alum-adjuvanted SCB-2019 vaccine for the prevention of any RT-PCR-confirmed COVID-19 of any severity in subjects without evidence of prior SARS-CoV-2 infection.
2. Primary Safety and Reactogenicity Objective: To assess the safety and reactogenicity of CpG 1018/Alum-adjuvanted SCB-2019 vaccine compared to placebo.
3. Primary Immunogenicity Objective: To demonstrate that SCB-2019 vaccine when given as a booster dose (full dose) elicits an immune response that is noninferior to the immune response when given as primary 2-dose series, as measured by virus neutralization assay at 14 days after third (booster dose) or second (primary 2-dose series) vaccination in subjects without evidence of prior SARS-CoV-2 infection.
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Protection of trial subjects |
The vaccine is cross-protective against D614G mutation SARS-CoV-2 strain, based on the hamster challenge study results which used the mut strain for challenge and VNT assay. Cross protection against SARS-CoV and other common cold coronaviruses are also being evaluated in nonclinical studies. The vaccine antigen is based on the full-length ectodomain spike (S1 and S2 domains), and S2 is more conserved across strains than S1.
The primary objective of the study was met:
• Two doses of SCB-2019 induced protection against COVID-19 of any severity in SARS-CoV-2–naïve adults with an efficacy of 67.2% (95.72% CI: 54.3–76.8).
The pre-specified success criteria were met for three of four key secondary efficacy objectives.
• The efficacy of 2 doses SCB-2019 against moderate-to-severe COVID-19 was 83.7% (97.86% CI 55.9–95.4) in SARS-CoV-2–naïve adults. The pre-specified success criterion (LL of multiplicity-adjusted CI above 0) was met.
• The efficacy of 2 doses SCB-2019 against severe COVID-19 was 100% (97.86% CI 25.3–100.0) in SARS-CoV-2–naïve adults. The pre-specified success criterion (LL of multiplicity-adjusted CI above 0) was met.
• The efficacy of 2 doses SCB-2019 against any laboratory-confirmed SARS-CoV-2 infection was 34.4% (95% CI: 27.1-41.0) in SARS-CoV-2-naïve adults. The pre-specified success criterion (LL of multiplicity-adjusted CI above 0) was met.
• The efficacy of 2 doses SCB-2019 against any laboratory-confirmed asymptomatic SARS-CoV-2 infection was 12.9% (95% CI: -1.4-25.2) in SARS-CoV-2-naïve adults. The pre-specified success criterion (LL of multiplicity-adjusted CI above 0) was not met.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Mar 2021
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Regulatory reason | ||
Long term follow-up duration |
12 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 709
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Country: Number of subjects enrolled |
Philippines: 13676
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Country: Number of subjects enrolled |
Colombia: 6696
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Country: Number of subjects enrolled |
Brazil: 7947
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Country: Number of subjects enrolled |
South Africa: 1100
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Worldwide total number of subjects |
30128
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EEA total number of subjects |
709
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
29712
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From 65 to 84 years |
416
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85 years and over |
0
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Recruitment
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Recruitment details |
Initially only healthy adult individuals 18-64 years of age were to be recruited in the study. After the review of post-Dose 1 safety data of approximately 200 healthy subjects aged 18-64 years, DSMB made a recommendation regarding the extension of recruitment and inclusion of older adults aged ≥65 years and individuals with comorbidities. | |||||||||
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Pre-assignment
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Screening details |
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. | |||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator | |||||||||
Blinding implementation details |
An unblinded team,not involved in evaluations,handled dose preparation and administration.Syringes were opacified and doses given behind a curtain to prevent unblinding.Study and sponsor staff monitoring the study were blinded to the vaccine code. Labs tests were also blinded to avoid linking samples with treatments.The treatment code could only be revealed for medical necessity. Unblinding required sponsor approval unless medically urgent.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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CpG 1018/alum/SCB-2019 group | |||||||||
Arm description |
approximately 15 000 adult subjects and 600 adolescents | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
CpG 1018/alum/SCB-2019
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Two i.m. injections, at Days 1 and 22.
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Arm title
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placebo arm | |||||||||
Arm description |
approximately 15 000 adult subjects and 600 adolescents | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
0.9% saline solution
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Two i.m. injections, at Days 1 and 22
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
CpG 1018/alum/SCB-2019 group
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Reporting group description |
approximately 15 000 adult subjects and 600 adolescents | ||
Reporting group title |
placebo arm
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Reporting group description |
approximately 15 000 adult subjects and 600 adolescents | ||
Subject analysis set title |
efficacy-PPS
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
For VE evaluation 14 days post Dose 2, subjects in the FAS - Efficacy (Dose 2) who correctly receive the full vaccination regimen and who have no other major protocol deviations that were judged to possibly impact the efficacy of the vaccine up to 14 days post Dose 2.
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Subject analysis set title |
efficacy-FAS (dose 2)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Vaccine Efficacy in SARS-CoV-2-exposed Subjects [Efficacy-FAS (Dose 2) Including only Subjects with Evidence of Prior SARS-CoV-2 Infection]
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Subject analysis set title |
phase 2-SAF
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Reactogenicity Subset
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Subject analysis set title |
immunogenicity PPS
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Subjects in the FAS – Immunogenicity who correctly receive the full vaccination regimen and who have no other major protocol deviations that were judged to possibly impact the immunogenicity of the vaccine
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Subject analysis set title |
immunogenicity FAS
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All adult subjects in the immunogenicity/reactogenicity subset and adolescent who are randomized, received at least one dose of study vaccine and provided immunogenicity data at Day 36 (Visit 3).
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End point title |
Primary Efficacy Objective (H1) - VE against COVID-19 of any severity | |||||||||||||||
End point description |
To demonstrate the efficacy of CpG 1018/alum-adjuvanted SCB-2019 vaccine for the prevention of any RT-PCR-confirmed COVID-19 of any severity in subjects without evidence of prior SARS-CoV-2 infection.
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End point type |
Primary
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End point timeframe |
13 Sep 2024
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Attachments |
CSR |
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Statistical analysis title |
Primary Efficacy Objective (H1) - VE against COVID | |||||||||||||||
Statistical analysis description |
This study had two stages: Phase 2 and Phase 3.
The primary endpoint for this study was defined as first occurrence of RT-PCR-confirmed COVID-19 of any severity, with onset at least 14 days after the second vaccination. The null (H10) and alternative (H1a) hypotheses for the primary endpoint are:
H10: VE ≤30% vs H1a: VE >30%.
The VE was to be calculated as 100×[1 – incidence rate ratio (IRR)].
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Comparison groups |
CpG 1018/alum/SCB-2019 group v placebo arm v efficacy-FAS (dose 2) v efficacy-PPS
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Number of subjects included in analysis |
56496
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||||||||
P-value |
< 0.05 | |||||||||||||||
Method |
exact Binomail | |||||||||||||||
Parameter type |
Mean difference (final values) | |||||||||||||||
Point estimate |
150
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
1-sided
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lower limit |
30 | |||||||||||||||
upper limit |
- | |||||||||||||||
Variability estimate |
Standard deviation
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| Notes [1] - The incidence rate (IR) for this study was defined as the number of subjects with any RT-PCR-confirmed COVID-19 of any severity divided by cumulative follow-up person time among all subjects at risk. multi Considering an attack rate of 0.60% per month (in the Placebo arm) for any COVID-19, and approximately 2 months follow-up or the primary efficacy endpoint, a total of 22 000 subjects, with randomization ratio 1:1, were to be enrolled assuming non-evaluability of 20% or less. |
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End point title |
Primary Safety and Reactogenicity Objective | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Solicited Local Reactions (Phase 2 SAF): ≤ 7-day after either dose
Solicited Systemic Adverse Events (Phase 2 SAF): ≤ 7-day after either dose
Unsolicited AEs between Day 1 and Day 43 (Phase 2 SAF): ≤ 6-week after 1st dose
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Statistical analysis title |
Primary Safety and Reactogenicity Objective | ||||||||||||
Comparison groups |
placebo arm v CpG 1018/alum/SCB-2019 group
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Number of subjects included in analysis |
29246
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Analysis specification |
Post-hoc
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Analysis type |
equivalence | ||||||||||||
P-value |
> 0.05 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Secondary immunogenicity objective | ||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
For WT-VNA titers (in IU/ml) and in the SCB-2019 recipients at Day 36, 2-weeks after the 2nd dose compare to the baseline on Day 1.
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| Notes [2] - SCB-2019 arm 381,Placebo 47 [3] - SCB-2019 arm 636,Placebo 84 |
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Statistical analysis title |
Secondary immunogenicity objective | ||||||||||||||||||||
Statistical analysis description |
In the Immunogenicity FAS, the SCB-2019 arm included 636 subjects, and the Placebo arm included 84 subjects. In the Immunogenicity PPS, the SCB-2019 arm included 381 subjects, and the Placebo arm included 47 subjects.
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Comparison groups |
immunogenicity PPS v immunogenicity FAS
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Number of subjects included in analysis |
1150
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||||||||||
P-value |
< 0.05 [5] | ||||||||||||||||||||
Method |
Clopper-Pearson | ||||||||||||||||||||
Confidence interval |
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| Notes [4] - The percentages (and 95% CIs) by arm of subjects seroconverted for (i) neutralizing Abs (measured by wild-type SARS-CoV-2 neutralization assay [{i} WT-VNA] and pseudovirus neutralizing assay [{ii} pseudo-VNA]); (iii) Abs that specifically block SCB-2019 spike protein from binding to hACE-2 (ACE2-receptor-binding Abs); and (iv) Abs specific for the SCB-2019 spike protein (SCB-2019–binding Abs); i.e., the seroconversion rates (SCRs). SCRs were calculated at Day 22 and Day 36. [5] - SCB-2019 spike protein (SCB-2019–binding Abs). GMTs were calculated at Day 1 (baseline), at Day 22 (21 days after Dose 1) and Day 36 (14 days after Dose 2). |
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Adverse events information
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Timeframe for reporting adverse events |
Local and systemic solicited AEs reported within 7 days after each study vaccination (in Phase 2 adult subjects and adolescents)
Unsolicited AEs reported from Visit 1 (Day 1) through Safety Call Day 43 (in Phase 2 adult subjects and adolescents)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||
Dictionary version |
26.1
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Reporting groups
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Reporting group title |
CpG 1018/alum/SCB-2019 group
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Reporting group description |
- | ||||||||||||||||||||||||||||||
Reporting group title |
placebo arm
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Reporting group description |
- | ||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0.03% | |||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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11 Apr 2022 |
Has updated Schedule of Activities, Objectives and Endpoints, Study Design, Contraindications to the Second or Third Vaccination, Inclusion Criteria, Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information, Pregnancy, Immunological Markers of SARS-CoV-2 Infection, Immunogenicity (Primary Objective), Analysis Timing. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
