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A Phase 2/3, Randomized, Observer-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of mRNA-1345, an mRNA Vaccine Targeting Respiratory Syncytial Virus (RSV), in Adults over 60 Years of Age

A Study to Evaluate the Safety and Efficacy of mRNA-1345 Vaccine Targeting Respiratory Syncytial Virus (RSV) in Adults over 60 Years of Age

818

Demographic and Baseline characteristics of the Randomization Set (which consisted of all participants who were randomized in the study, regardless of the participants study intervention administration status) were balanced between the 2 groups. Mean (standard deviation [SD]) participant age was 68.5 (6.60) years (68.5 [6.61] years and 68.5 [6.59] years in the placebo and mRNA-1345 groups, respectively). A total of: -18074/36814 (49.1%) participants were female (9057/18387 [49.3%] and 9017/18427 [48.9%] participants in the placebo and mRNA-1345 groups, respectively), and -18740/36814 (50.9%) participants were male (9330/18387 [50.7%] and 9410/18427 [51.1%] participants in the placebo and mRNA-1345 groups, respectively). The majority of participants were White (61.4%) and Not Hispanic or Latino (65.6%).

Part A: A total of 36814 participants were randomized (18387 participants in the placebo group and 18427 participants in the mRNA-1345 group). Of these, 36685 participants received study intervention (18316 in the placebo group and 18369 in the mRNA-1345 group). A total of 2782 participants in the placebo group and 2701 participants in the mRNA-1345 group discontinued from Part A of the study. Overall, the most frequent primary reason for discontinuation was withdrawal of consent by participant (1781 participants), followed by lost to follow-up (1720 participants), and other (1067 participants). 179 participants were discontinued due to physician decision, 79 participants were discontinued due to protocol violation, 49 participants were discontinued due to an adverse event (AE), and 3 participants were discontinued due to non-compliance with study drug. A total of 605 participants died from any cause (300 in the mRNA-1345 group versus 305 in the placebo group). Part B: A total of 1510 participants from Part A mRNA-1345 group were randomized in Part B (505 participants in the placebo group and 1005 participants in the mRNA-1345 group). Of these, 1502 participants received a revaccination injection (504 in the placebo group and 998 in the mRNA-1345 group). A total of 76 participants discontinued from Part B of the study. 1 participant died in the placebo group and no deaths were reported in the mRNA-1345 revaccination group. No other participants discontinued due to an AE or solicited AR. The most common reasons for discontinuation were other (45 participants), lost to follow-up (18 participants), and withdrawal of consent (12 participants).

Part A: -The number of participants reporting unsolicited AEs up to the end of study (EOS) in Part A were balanced between the groups (13389 participants [72.9%] in the mRNA-1345 group versus 13089 [71.5%] in the placebo group). -The participant incidence of fatal events was balanced between the mRNA-1345 and placebo groups up to the EOS in Part A. None of the fatal events were assessed as related to study injection. A total of 301 participants (1.6%) in the mRNA-1345 group and 307 participants (1.7%) in the placebo group died from any cause. -Up to the EOS in Part A, SAEs regardless of causality were reported for 2773 participants (15.1%) in the mRNA-1345 group and 2745 participants (15.0%) in the placebo group. SAEs that were assessed as related to study injection were reported for 4 participants in the mRNA-1345 group and 4 participants in the placebo group (each <0.1%). Part B: -No mRNA-1345 participants died during Part B of the study. 1 participant (0.2%) in the placebo group died 86 days after the revaccination injection. -Up to EOS after revaccination, 29 participants (2.9%) in the mRNA-1345 group versus 26 participants (5.2%) in the placebo group experienced SAEs. No participants in the mRNA-1345 group and 1 participant in the placebo group experienced SAEs assessed as related to study injection by the Investigator.

-Primary Endpoint 1: Part A: Number of Participants with Solicited Local and Systemic Adverse Reactions (ARs). Analysis was performed on Part A Solicited Safety Set that included all randomized participants who received the study intervention and who contributed any solicited AR data. Participants were included in the treatment group corresponding to the study vaccination that they actually received. The incidence of any solicited AR within 7 days after study vaccine in Part A was 6975/18102 (38.5%) participants in the placebo group and 12383/18174 (68.1%) participants in the mRNA-1345 group. -Primary Endpoint 2: Part B: Number of participants with solicited local and systemic ARs. Analysis was performed on Part B Solicited Safety Set that included all Part B randomized participants who received any study intervention and contributed any solicited AR data. Participants were included in the treatment group corresponding to the study vaccination that they actually received. The incidence of any solicited AR within 7 days after booster dose (BD) injection in Part B was 194/503 (38.6%) participants in the placebo group and 748/995 (75.2%) participants in the mRNA-1345 group. -Primary Endpoint 3: Part A: Number of Participants with Unsolicited Adverse Events (AEs). Analysis was performed on Part A Safety Set that included all randomized participants who received any study intervention. Participants were included in the treatment group corresponding to the study vaccination that they actually received. The incidence of any unsolicited AE within 28 days after study vaccine was 3472/18316 (19.0%) participants in the placebo group and 3841/18369 (20.9%) participants in the mRNA-1345 group. -Primary Endpoint 4: Part B: Number of Participants with Unsolicited AEs. Analysis was performed on Part B Safety Set that included all Part B randomized participants who received any study intervention. Participants were included in the treatment group corresponding to the study vaccination that they actually received. The incidence of any unsolicited AE within 28 days after BD injection was 75/504 (14.9%) participants in the placebo group and 123/998 (12.3%) participants in the mRNA-1345 group. -Primary Endpoint 5: Part A: Number of Participants with Medically Attended AEs (MAAEs), Adverse Events of Special Interest (AESIs), Serious Adverse Events (SAEs), and AEs Leading to Study Discontinuation up to 24 Months Postinjection. Analysis was performed on Part A Safety Set that included all randomized participants who received any study intervention. Participants were included in the treatment group corresponding to the study vaccination that they actually received. The MAAEs were reported in 10995/18316 (60.0%) participants in the placebo group and 11313/18369 (61.6%) participants in the mRNA-1345 group. SAEs were reported in 2745/18316 (15.0%) participants in the placebo group and 2773/18369 (15.1%) participants in the mRNA-1345 group. AEs leading to discontinuation were reported in 335/18316 (1.8%) participants in the placebo group and 319/18369 (1.7%) participants in the mRNA-1345 group. AESIs were reported in 154/18316 (0.8%) participants in the placebo group and 158/18369 (0.9%) participants in the mRNA-1345 group. -Primary Endpoint 6: Part B: Number of Participants with MAAEs, AESIs, SAEs, and AEs Leading to Study Discontinuation up to BD Day 181. Analysis was performed on Part B Safety Set that included all Part B randomized participants who received any study intervention. Participants were included in the treatment group corresponding to the study vaccination that they actually received. The MAAEs were reported in 131/504 (26.0%) participants in the placebo group and 226/998 (22.6%) participants in the mRNA-1345 group. SAEs were reported in 26/504 (5.2%) participants in the placebo group and 29/998 (2.9%) participants in the mRNA-1345 group. AEs leading to discontinuation were reported in 1/504 (0.2%) participants in the placebo group and 0/998 participants in the mRNA-1345 group. AESIs were reported in 3/504 (0.6%) participants in the placebo group and 2/998 (0.2%) participants in the mRNA-1345 group. -Primary Endpoint 7: Part A: Vaccine efficacy (VE) of mRNA-1345 to Prevent First Episode of Respiratory Syncytial Virus-Associated Lower Respiratory Tract Disease (RSV-LRTD) (With 2 or More Symptoms or 3 or More Symptoms) between 14 days after Injection up to 12 Months after Injection. Analysis was performed on Part A PPE Set: all randomized participants who received assigned study intervention according to protocol, completed >=1 visit or surveillance contact 14 days after study intervention administration, and had no major protocol deviations affecting the efficacy outcomes as determined prior to database lock and unblinding. Participants were analyzed according to vaccination group to which they were randomized. VE against RSV-LRTD with >=3 symptoms was 82.4% and the lower bound (LB) of the 96.36% confidence interval (CI) was 34.8%, exceeding the prespecified success criterion of >20%. VE against RSV-LRTD with >=2 symptoms was 83.7% and LB of the 95.88% CI was 66.0%, exceeding the prespecified success criterion of >20%. -Primary Endpoint 8: Part B: Geometric Mean Titer (GMT) of Serum Respiratory Syncytial Virus Subtype A (RSV-A) and Respiratory Syncytial Virus Subtype B (RSV-B) Neutralizing Antibodies (nAb) at BD Day 29 Compared to Primary Dose Day 29. Analysis was performed on Part B Per-protocol (PP) Set that included all Part B randomized participants who received both Parts A and B assigned study intervention doses, had RSV immunogenicity titer results at pre-Primary Dose (baseline), had RSV immunogenicity titer results at Primary Dose Day 29, had at least 1 valid result at Revaccination Day 29, and had no major protocol deviations affecting the primary immunogenicity outcomes as determined prior to database lock and unblinding. Participants were analyzed according to the study intervention group to which they were randomized. The GMR of revaccination Day 29 GMT over post primary vaccination Day 29 GMT for RSV-A and RSV-B nAbs were 0.719 (95% CI: 0.676, 0.764) and 0.705 (95% CI: 0.6671, 0.7444), respectively, meeting the noninferiority criterion of LB 95% CI >0.667 (1/1.5).

A single dose of mRNA-1345 demonstrated VE through 24 months in adults >=60 years of age. No safety issue of concern was identified during long-term follow-up through 24 months. Post revaccination immune responses at 24 months were non-inferior to that observed post primary vaccination. Revaccination at 24 months was well tolerated with no new safety concerns.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031220274

Azuma Yuki

PPD-SNBL K.K.

St Luke's Tover 12F, 8-1 Akashi-cho, Chuo-ku, Tokyo

yuki.azuma@thremofisher.com

Azuma Yuki

PPD-SNBL K. K.

St Luke's Tover 12F, 8-1 Akashi-cho, Chuo-ku, Tokyo

+81-90-9596-2021

yuki.azuma@thremofisher.com

Complete

Aug. 29, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

prevention purpose

Adults over 60 years of age who are primarily responsible for self-care and activities of daily living. Participants may have one or more chronic medical diagnoses (specifically chronic heart failure [CHF] and chronic obstructive pulmonary disease [COPD]), but should be medically stable as assessed by the following criteria: absence of changes in medical therapy within 1 month due to treatment failure or toxicity; absence of medical events qualifying as SAEs within 1 month of the planned study injection on Day 1; and absence of known, current, and life-limiting diagnoses, which could continue for the duration of the primary efficacy period (12 months from study injection on Day 1) and which, in the opinion of the investigator, would make completion of the protocol unlikely.

Body mass index from over18 kilograms(kg)/square meter (m2) to under 35 kg/m2.

Participation in another clinical research study where participant has received an investigational product (drug/biologic/device) within 45 days before the planned date of the Day 1 vaccination.

Prior participation in research involving receipt of any investigational RSV product (drug/biologic/device).

History of a serious reaction to any prior vaccination or Guillain-Barre syndrome within 6 weeks of any prior influenza immunization.

Received or plans to receive any nonstudy vaccine (including authorized or approved vaccines for the prevention of COVID-19 regardless of type of vaccine) within 28 days before or after the Day 1 study injection. Nonstudy vaccination(s) should not be delayed.

Both

Prevention of infections caused by Respiratory Syncytial virus

Participants will be randomly assigned to receive a single injection of either mRNA-1345 vaccine at the selected dose or placebo in a 1:1 randomization ratio. Investigational product will be administered as a single IM injection on Day 1. The injection will have a volume of 0.5 mL and contains mRNA-1345 or saline placebo.

Safety Endpoint:
Numbers and percentages of participants with solicited local and systemic adverse reactions (ARs) up to 7 days postinjection.

Number of participants with unsolicited adverse events (AEs) up to 28 days postinjection.

Number of participants with medically attended adverse events (MAAEs), adverse events of special interest (AESIs), serious adverse events (SAEs), and AEs leading to withdrawal up to 24 months postinjection.

Efficacy Endpoint:
Vaccine efficacy of mRNA-1345 to prevent a first episode of RSV-LRTD with 2 or more symptoms within the period of 14 days post-injection up to 12 months post-injection.

Vaccine efficacy of mRNA 1345 to prevent a first episode of RSV-LRTD with 3 or more symptoms within the period of 14 days post injection up to 12 months post-injection.

Key Secondary Efficacy Endpoints:
Vaccine efficacy of mRNA 1345 to prevent a first episode of RSV ARD within the period of 14 days post injection up to 12 months post-injection.

Vaccine efficacy of mRNA 1345 to prevent first hospitalization associated with RSV ARD or RSV LRTD within the period of 14 days post injection up to 12 months post-injection.

+81-3-6804-2227

July. 05, 2022

Argentina/Australia/Belgium/Brazil/Canada/Chile/Colombia/Costa Rica/Finland/Germany/Mexico/Netherlands/New Zealand/Panama/Poland/Puerto Rico/Singapore/South Africa/South Korea/Spain/Taiwan/UK/USA