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A phase1/2 trial of SARS-CoV-2 self-amplifying RNA vaccine VLPCOV-02 with a booster dose to evaluate safety, tolerability, immunogenicity, and optimal dose in healthy subjects

A phase 1/2 trial of booster dose of VLPCOV-02 vaccine

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Part1 In the FAS (All subjects who met the protocol's entry criteria), the percentage of male subjects in the non-elderly and elderly cohorts was 33.3% to 66.7% in the VLPCOV-02 1 ug, 3 ug, 7.5 ug, and 15 ug groups. The average age was 50.8 to 54.0 years for non-elderly subjects and 67.5 to 68.7 years for elderly subjects. Part 2 In the FAS, the percentage of male subjects in the non-elderly and elderly cohorts was 50.0% to 61.8% in the VLPCOV-02 3 ug or 7.5 ug, and Comirnaty RTU Intramuscular Injection (bivalent: Original/Omicron BA.4-5) 30 ug. The average age was 50.6 to 52.9 years for non-elderly subjects and 69.1 to 70.6 years for elderly subjects.

Part 1 Primary Analysis (up to 4 weeks(Day 29)after study drug inoculation) Of the 174 subjects who gave written informed consent, 48 non-elderly and 48 elderly subjects were enrolled from the subjects confirmed to be eligible, and all of them completed inoculation with the study drug. Twelve non-elderly and twelve elderly subjects each received VLPCOV-02 1 ug, 3 ug, 7.5 ug, or 15 ug. All subjects completed the study until 4 weeks (Day 29) after inoculation, and no subjects were discontinued or dropped out. Secondary Analysis (up to 52 weeks (Day 365) after study drug inoculation) After 4 weeks after study drug inoculation, one elderly subject from each of the VLPCOV-02 3 ug and 7.5 ug groups dropped out due to meeting the criterion: 'If the subject received or wished to receive any approved SARS-CoV-2 vaccines after study drug inoculation'. All other subjects completed up to 52 weeks after inoculation. Part 2 Primary Analysis (up to 4 weeks (Day 29) after study drug inoculation) Of the 336 subjects who gave written informed consent, 160 non-elderly and 163 elderly subjects for whom eligibility was confirmed during screening were randomized. All randomized subjects completed study drug inoculation, and 53, 55, and 52 non-elderly and 54, 55, and 54 elderly subjects were inoculated with VLPCOV-02 3 ug, 7.5 ug, and Comirnaty RTU 30 ug, respectively. By 4 weeks after inoculation, 1 non-elderly subject in the VLPCOV-02 3 ug group and 1 non-elderly subject in the Comirnaty RTU 30 ug group met the criteria 'If the subject was unable to visit the site for reasons such as relocation, accident, etc. and failed to undergo sufficient tests at the specified times' and 'If the subject voluntarily withdrew consent,' and dropped out. All other subjects completed up to 4 weeks after inoculation. Secondary Analysis (26 and 52 weeks (Day 183 and Day 365) after study drug inoculation) Between 4 weeks and 26 weeks after study drug inoculation, 2, 2, and 0 non-elderly subjects, and 1, 0, and 2 elderly subjects in the VLPCOV-02 3 ug, 7.5 ug, and Comirnaty RTU 30 ug groups, respectively (same order in the following), were dropped out. The reasons for dropout were either: 'If the subject voluntarily withdrew consent' (3 subjects in the VLPCOV-02 group), or 'If the subject received or wished to receive any approved SARS-CoV-2 vaccines after study drug inoculation' (2 subjects in the VLPCOV-02 group and 2 subjects in the Comirnaty RTU 30 ug group). Between 26 weeks and 52 weeks after study drug inoculation, 1, 1, and 0 non-elderly subjects, and 0, 2, and 1 elderly subjects in the VLPCOV-02 and Comirnaty RTU 30 ug groups, respectively, were dropped out. The reasons for dropout were either 'If the investigator or sub-investigator determined that the subject is unable to comply with the Protocol' (1 subject in the VLPCOV-02 group), 'If the subject was unable to visit the site for reasons such as relocation, accident, etc. and failed to undergo sufficient tests at the specified times' (2 subjects in the VLPCOV-02 group), or 'If the subject received or wished to receive any approved SARS-CoV-2 vaccines after study drug inoculation' (1 subject in the VLPCOV-02 group and 1 subject in the Comirnaty RTU 30 ug group). All other subjects completed through 52 weeks after inoculation.

Part 1 During the study period up to 52 weeks after study drug inoculation, no safety concerns were observed and tolerability was favorable in both non-elderly and elderly subjects with respect to serious adverse events, COVID-19 adverse events, and adverse events leading to discontinuation of the study. -The severity of most of the solicited adverse events was mild to moderate and resolved in a short period of time. -There was no large difference in the incidence of solicited local adverse events between all groups. -The incidence of solicited systemic adverse events increased in accordance with the inoculation dose, and especially in the 15 ug group, the incidence and severity of almost all symptoms increased. -Serious adverse events did not occur in any group. -Adverse events occurred in 22 subjects (91.7%) and 23 subjects (95.8%) in the VLPCOV-02 1 ug and 3 ug groups, respectively, and in all 24 subjects (100.0%) in the 7.5 ug and 15 ug groups. The incidence of adverse reactions was the same as that of adverse events. - Almost all adverse events were events reported as solicited adverse events. Other adverse events that were not solicited events and were reported in more than 1 subject overall were increased C-reactive protein (3 subjects; related) and increased blood creatine phosphokinase (3 subjects; not related). Adverse events reported in only 1 subject overall and considered to be adverse reactions were palpitations, rash, itching at the vaccination site, and decreased neutrophil count. - With the exception of the adverse events of decreased neutrophil count, increased C-reactive protein, and palpitations (all of which were causally related to the study drug and mild), there were no clinically significant changes in laboratory values, vital signs, and 12-lead ECG. Part2 During the study period up to 52 weeks after study drug inoculation, no safety concerns were observed and tolerability was favorable in both non-elderly and elderly subjects with respect to serious adverse events, COVID-19 adverse events, and adverse events leading to discontinuation of the study. -The severity of most solicited adverse events was mild to moderate. -The incidence of solicited local adverse events was similar in all groups in both non-elderly and elderly subjects. In non-elderly subjects, the incidence of severe adverse events was similar in all groups, but the incidence of moderate adverse events was higher in the VLPCOV-02 7.5 ug group than in the 3 ug group, and similar in the VLPCOV-02 3 ug group and Comirnaty RTU 30 ug group. In the elderly, the incidence of severe and moderate events was similar in all groups. -The incidence of solicited systemic adverse events overall was higher in the VLPCOV-02 7.5 ug group than in the 3 ug group in both non-elderly and elderly subjects for fatigue, headache, fever, chills, arthralgia, and nausea, and the incidence in the VLPCOV-02 3 ug group was similar to that in the Comirnaty RTU 30 ug group. The incidence of severe and moderate events in both non-elderly and elderly subjects was higher in the VLPCOV-02 7.5 ug group than in the 3 ug group, and similar in the VLPCOV-02 3 ug group and Comirnaty RTU 30 ug group. While moderate and severe events of fever in all age cohorts were noted in 13 subjects (11.8%) in the VLPCOV-02 7.5 ug group and in 5 subjects (4.7%) in the Comirnaty RTU 30 ug group, no events were noted in the VLPCOV-02 3 ug group.

Part 1 A study was conducted on non-elderly and elderly healthy Japanese men and women adult using a single study drug inoculation of VLPCOV-02 at 1 ug, 3 ug, 7.5 ug, and 15 ug. Demonstrated at 4 weeks after study drug inoculation that a single booster dose of VLPCOV-02 at all doses induced immunogenicity towards serum IgG antibody titers against the SARS-CoV-2 RBD protein in both non-elderly and elderly subjects. After 4 weeks of study drug inoculation, IgG titers gradually declined by 52 weeks in both groups for both non-elderly and elderly subjects. Part 2 The immunogenicity at 4 weeks after a single inoculation of either study drug was investigated in healthy Japanese adults (non-elderly and elderly), who received either VLPCOV-02 at 3 ug or 7.5 ug, or Comirnaty RTU Intramuscular Injection (bivalent: Original/Omicron BA.4-5) 30 ug. As an important indicator for measuring the outcomes of the trial, the primary endpoint was the " elevated serum-neutralizing antibody titers against Omicron BA.5," and the primary endpoint up to 4 weeks after the study drug inoculation was confirmed. As a result, both in non-elderly and elderly subjects, the VLPCOV-02 3 ug and 7.5 ug groups demonstrated immunogenicity comparable to that of the Comirnaty RTU 30 ug group. Regarding the trend in GMT of serum neutralizing antibody titers against the Omicron BA.5 after 4 weeks or more following the study drug inoculation, in both non-elderly and elderly subjects, GMT gradually decreased from 26 weeks after the study drug inoculation until 52 weeks, but a higher trend was observed in both groups of VLPCOV-02 compared to the Comirnaty RTU 30 ug group. In addition, an increase in neutralizing antibody titers against all virus strains except the Omicron BA.5 strain (the original strain, Gamma variant, Omicron XBB.1.5) was confirmed up to 4 weeks after the study drug inoculation. In both non-elderly and elderly participants, similar immunogenicity to the Comirnaty RTU 30 ug group was confirmed in both VLPCOV-02 groups. The neutralizing antibody titers against all virus strains except the Omicron BA.5 strain also showed a similar trend to that of the Omicron BA.5 variant from 4 weeks after the investigational drug inoculation up to 52 weeks. Serum-neutralizing antibody titer against pseudovirus showed a similar trend.

In Part 1, no safety concerns were observed up to 4 weeks after a single VLPCOV-02 booster at 1, 3, 7.5, or 15 ug in both non elderly and elderly subjects, and tolerability up to 15 ug was confirmed. Immunogenicity was confirmed at all doses. Because 15 ug caused more systemic solicited adverse events, 3 and 7.5 ug were used in Part 2. Both doses demonstrated immunogenicity comparable to Comirnaty RTU 30 ug, and safety favored 3 ug.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2051230005

Aboshi Masayuki

VLP Therapeutics Japan, Inc.

Hilton Plaza West Office Tower, 2-2-2 Umeda Kita-ku, Osaka city, Osaka

clinical@vlptherapeutics.com

Aboshi Masayuki

VLP Therapeutics Japan, Inc.

Hilton Plaza West Office Tower, 2-2-2 Umeda Kita-ku, Osaka city, Osaka

+81-70-8336-6345

clinical@vlptherapeutics.com

Complete

April. 10, 2023

Interventional

randomized controlled trial

double blind

active control

parallel assignment

prevention purpose

(1) Aged 18 years or older at the time of obtaining consent
(2) Aged 75 years or younger at the time of obtaining consent (Part 1 only)
(3) Signed written informed consent for participation in this study
(4) Able to comply with the rules during participating in the study, receive tests and physical examinations prespecified in the study protocol, complete the electronic diary (e-Diary) themselves, and report such as their symptoms
(5) Received the 2-dose primary vaccination series with the same SARS-CoV-2 uridine modified RNA vaccine ('mRNA vaccine,' thereafter), or received a booster inoculation with mRNA vaccine (any kind of mRNA vaccine and number of booster inoculations, including bivalent mRNA vaccine) following receiving the 2-dose primary vaccination series with the same mRNA vaccine
(6) Six months or more elapsed from previous SARS-CoV-2 vaccination on the scheduled day of study drug inoculation
(7) The body mass index (BMI) is 18.0 kg/m2 or more and 35 kg/m2 or less at Visit 00 (Part 1 only)

(1) Any flulike symptom (findings suggestive of infection, such as fever at axillary body temperature of 37.5 degrees or more, chill, cough, nasal discharge, headache, myalgia) within 72 hours before study drug inoculation
(2) Positive SARS-CoV-2 antigen test result prior to study drug inoculation on Visit 01 (Day 1)
(3) History of SARS-CoV-2 infection (including asymptomatic and deemed positive) within 6 months prior to Visit 01 (Day 1)
(4) Complication or known history of serious cardiovascular (including thrombosis), hematological, respiratory, hepatic, renal, gastrointestinal, and/or psychoneurological disease (Part 1 only)
(5) Complication of unstable serious cardiovascular (including thrombosis), hematologic, respiratory, hepatic, renal, gastrointestinal, and/or psychoneurological disease (Part 2 only)
' Unstable' is defined as: having undergone surgery or invasive procedures within 3 months prior to screening for this study, having required a change in therapeutic agent, etc. associated with a worsening of disease status, or having any of the above planned during the study period.
(6) Complication of an active infection
(7) Disease or status, or a known history deemed to interfere with the evaluation of the immunogenicity of the study drug, such as immunodeficiency and autoimmune disease
(8) Received an agent or therapy deemed to interfere with the evaluation of the immunogenicity of the study drug, or having a schedule to receive the above during participating in the study
(9) History of anaphylaxis or severe allergy in the past by food or pharmaceutical agents (including vaccine), etc.
(10) History of convulsion (excluding febrile seizure), Guillain-Barre syndrome, or acute disseminated encephalomyelitis
(11) Experienced a long-lasting (approximately 2 weeks as a guide) symptom of any kind from vaccination against SARS-CoV-2 or SARS-CoV-2 infection in the past
(12) Females who do not agree to use appropriate contraception methods through 90 days after study drug inoculation
(13) Pregnant or lactating females or those who intend to become pregnant through 90 days after study drug inoculation
(14) Participation in other clinical study within 3 months prior to screening of this study, or are scheduled to be participated in other clinical study, etc. during participating in this study
(15) Bleeding tendency, and for whom the principal investigator or sub-investigator determined intramuscular inoculation to be a contraindication
(16) Ineligible by the principal investigator or sub-investigator for participating in this study

Both

Prevention of infectious disease caused by SARS-CoV-2

Drug: VLPCOV-02
Administered IM
Drug: COMIRNATY RTU intramuscular injection (Bivalent: Original/Omicron BA.4-5)
Administered IM

Study Arms
-Experimental:VLPCOV-02 Dose 1
VLPCOV-02 given IM injections
Intervention: Drug: VLPCOV-02

-Experimental:VLPCOV-02 Dose 2
VLPCOV-02 given IM injections
Intervention: Drug: VLPCOV-02

-Active Comparator: COMIRNATY RTU intramuscular injection
COMIRNATY RTU intramuscular injection given IM injections
Intervention: Drug: COMIRNATY RTU intramuscular injection

(Part 1)
Safety
1. Incidence and severity of the following adverse events:
(1) Solicited local adverse events which occurred through 7 days after study drug inoculation
(2) Solicited systemic adverse events which occurred through 7 days after study drug inoculation
(3) Adverse events which occurred through 4 weeks after study drug inoculation
Immunogenicity
1. At Week 4 after study drug inoculation:
(1) GMT of serum IgG titers against SARS-CoV-2 RBD protein
(2) SRR of serum IgG titers against SARS-CoV-2 RBD protein
(Part 2)
Immunogenicity
1. At Week 4 after study drug inoculation:
(1) GMT of serum neutralizing antibody titers against live virus (Omicron BA.5)
(2) SRR of serum neutralizing antibody titers against live virus (Omicron BA.5)
Safety
1. Incidence and severity of the following adverse events:
(1) Solicited local adverse events which occurred through 7 days after study drug inoculation
(2) Solicited systemic adverse events which occurred through 7 days after study drug inoculation
(3) Adverse events which occurred through 4 weeks after study drug inoculation

+81-6-6395-9000

Mar. 23, 2023

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