E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Invasive Extraintestinal Pathogenic Escherichia coli Disease |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052238 |
E.1.2 | Term | Escherichia urinary tract infection |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10015295 |
E.1.2 | Term | Escherichia infections |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate in a hierarchical manner:
- the efficacy of ExPEC9V compared to placebo in the prevention of the first IED event with
microbiological confirmation from blood, other sterile sites, or urine caused by ExPEC serotypes O1A, O2, O4, O6A, O15, O16, O18A, O25B, and O75 and
- the efficacy of ExPEC9V compared to placebo in the prevention of the first IED event with microbiological confirmation from blood or other sterile sites caused by ExPEC serotypes O1A, O2, O4, O6A, O15, O16, O18A, O25B, and O75 |
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E.2.2 | Secondary objectives of the trial |
To demonstrate the efficacy of ExPEC9V compared to placebo in the prevention of
•all IEDs caused by ExPEC9V O-serotypes
•the first hospitalized IED event caused by ExPEC9V O-serotypes
•the first IED event meeting criteria for sepsis caused by ExPEC9V O-serotypes
•the first bacteremic IED event caused by ExPEC9V O-serotypes
•the first pyelonephritis event caused by ExPEC9V O-serotypes
•the first UTI event caused by ExPEC9V O-serotypes
•all UTIs caused by ExPEC9V O-serotypes
•the first IED event caused by any ExPEC O-serotype
•the first pyelonephritis event caused by any ExPEC O-serotype
•the first UTI event caused by any ExPEC O-serotype
To evaluate:
•the immunogenicity of ExPEC9V in the Immunogenicity Subset
•the safety and reactogenicity of ExPEC9V
•the preservation of health status and health-related quality of life (HRQoL) of ExPEC9V compared to placebo
the impact of IED and UTI, caused by ExPEC9V O-serotypes, on physical and mental health, and overall HRQoL
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Participant must be ≥60 years of age on the day of signing the ICF and is expected to be available for the duration of the study, with no current intention of moving away from a study site area or travelling for periods longer than 30 consecutive days during the course of the study.
-Participant must have a history of UTI in the past 2 years that is documented in the medical records. In case of a recent history of UTI, the condition must have resolved >14 days prior to randomization.
-Participant must be medically stable at the time of vaccination such that, according to the judgment of the investigator, hospitalization within the study period is not anticipated and the participant appears likely to be able to remain on study through the end of protocol-specified follow-up. A stable medical condition is defined as disease not requiring significant change in therapy during the 6 weeks before enrollment and when hospitalization for worsening of the disease is not anticipated. Participants will be included on the basis of physical examination, medical history, and vital signs performed between ICF signature and vaccination.
-Before randomization, participants who were born female must be either (as defined in Section 10.4, Appendix 4, Contraceptive Guidance and Collection of Pregnancy Information):
a. postmenopausal or permanently sterile, and
b. not intending to conceive by any methods.
-Participant must be willing to provide verifiable identification, has means to be contacted and to contact the investigator during the study.
-Participant or his/her designated caregiver must be able to work with smartphones/tablets/computers.
-Participant and his/her designated caregiver (if applicable) must be able to read, understand, and complete questionnaires in the eCOA (ie, the electronic patient-reported outcomes [ePROs] and the eDiary).
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E.4 | Principal exclusion criteria |
-Participant has a serious chronic disorder or significant cognitive impairment for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise well-being) or that could prevent, limit, or confound the protocol-specified assessments.
- Participant has end-stage renal disease for which dialysis is required.
- Chronic use of antimicrobials. In case of prolonged antimicrobial treatment (>3 weeks) or chronic use of antimicrobials, the last dose must have been administered >60 days prior to randomization.
- Participant has a history of malignancy within 5 years before screening not in the following categories:(a) Participants with squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix may be enrolled at the discretion of the investigator; (b) Participants with diagnosis of localized prostate cancer may be enrolled at the discretion of the investigator if they completed treatment, or, if they remain under observation or active surveillance; (c) Participants with a history of other malignancy within 5 years, which is considered adequately treated with minimal risk of recurrence per the investigator’s judgment, may be enrolled.
- Participant has a known allergy or history of anaphylaxis or other serious adverse reactions to vaccines or their excipients (including specifically the excipients of the study vaccine; refer to IB).
- Abnormal function of the immune system resulting from:
a. Clinical conditions (eg, autoimmune disease or immunodeficiency).
b. Chronic or recurrent use of systemic corticosteroids
c. Administration of antineoplastic and immunomodulating agents or radiotherapy.
- Participant has a history of acute polyneuropathy (eg, Guillain-Barré syndrome) or chronic inflammatory demyelinating polyneuropathy
- Participant has received any E. coli or ExPEC vaccine.
- Participant has received a hematopoietic stem cell transplant based on medical history, treatment with immunoglobulins within 2 months, apheresis therapies within 4 months, or blood products within 4 months prior to the planned administration of the study vaccine or has any plans to receive such treatment during the study.
- Participant has received or plans to receive: (a)licensed live attenuated vaccines - within 28 days before or after planned administration of the study vaccination; (b)other licensed (not live) vaccines - within 14 days before or after planned administration of the study vaccination; (c)vaccination with a licensed or authorized for Emergency Use Authorization, conditional Marketing Authorisation or a similar program) COVID-19 vaccine is permitted when given at least 28 days before or after planned administration of the study vaccination.
- Participant has had major surgery (per the investigator’s judgment) within 4 weeks before dosing or will not have recovered from surgery per the investigator’s judgment at time of vaccination.
- Participant has chronic active hepatitis B or hepatitis C infection based on medical history. Note: participant may have stable HBV or HCV infection.
- Participant has evidence of HIV type 1 or type 2 infection by medical history. Note: participant may have stable/well-controlled HIV.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary analysis of the primary endpoints will evaluate:
• the number of participants with at least 1 IED event, with microbiological confirmation in blood, other sterile sites, or urine, caused by ExPEC serotypes O1A, O2, O4, O6A, O15, O16, O18A, O25B, and O75 with onset at least 29 days after vaccination (from Day 30) in the active vaccine (ExPEC9V) group compared to the placebo group in the PPE population and
• the number of participants with at least 1 IED event with microbiological confirmation in blood or other sterile sites caused by ExPEC serotypes O1A, O2, O4, O6A, O15, O16, O18A, O25B, and O75 with onset at least 29 days after vaccination (from Day 30) in the active vaccine (ExPEC9V) group compared to the placebo group in the PPE population.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• First IED event , with microbiological confirmation from blood, other sterile sites, or urine, caused by ExPEC9V O serotypes O1A, O2, O4, O6A, O15, O16, O18A, O25B, and O75
•First IED event, with microbiological confirmation from blood or other sterile sites, caused by ExPEC9V O serotypes
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E.5.2 | Secondary end point(s) |
•All IEDs (including multiple IEDs per participant) caused by ExPEC9V O serotypes
• First hospitalized IED event caused by ExPEC9V O serotypes
• First IED event meeting criteria for sepsis caused by ExPEC9V O serotypes
• First bacteremic IED event caused by ExPEC9V O serotypes
• First pyelonephritis event caused by ExPEC9V O serotypes
• First UTI event caused by ExPEC9V O serotypes
• All UTIs (including multiple UTIs per participant) caused by ExPEC9V O serotypes
• First IED event caused by any ExPEC O serotype
• First pyelonephritis event caused by any ExPEC O-serotype
• First UTI event caused by any ExPEC O serotype
• Antibody titers to vaccine O-serotype antigens in the Immunogenicity Subset, as determined by multiplex ECL-based immunoassay and multiplex opsonophagocytic killing assay (MOPA) on Day 30, Day 181, Year 1, Year 2, and Year 3
• Solicited local and systemic AEs (collected until 14 days post-vaccination [from Day 1 to Day 15] in the Safety Subset)
• Unsolicited AEs (collected until 29 days post-vaccination [from Day 1 to Day 30] in all participants)
• Serious adverse events (SAEs) in all participants
• SF-36 and EQ-5D-5L responses at scheduled timepoints
• Frailty index as a measure of frailty at baseline, Year 1, Year 2, Year 3, and at the time of an IED
• Medical resource utilization for IED events
• Medical resource utilization for UTI events (Immunogenicity Subset only)
• Hospitalization and length of stay in hospital for IED or UTI events
• IED-related and all-cause mortality
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As described in section E.5.2 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Japan |
Korea, Republic of |
New Zealand |
United States |
Denmark |
Netherlands |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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If Part 2 of the study is not conducted, the end of study is considered as the last Year 3 assessment (Day 1096) for the last participant in Part 1. If Part 2 of the study is conducted, the end of study is considered as the last Year 3 assessment (Day 1096) for the last participant in Part 2. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |