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 O1, O2, O4, O6, O15, O16, O18, O25, 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 O1, O2, O4, O6, O15, O16, O18, O25, 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 E.coli
•the first pyelonephritis event caused by any E.coli
•the first UTI event caused by any E.coli
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 for which evidence of diagnosis was verified by investigator. In case of a recent history of UTI or ABP (acute bacterial prostatitis), 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 and his/her designated caregiver (if applicable) must be able to read, understand, and complete questionnaires in the electronic clinical outcome assessment system (eCOA, ie, the electronic patient-reported outcomes [ePROs] and the eDiary). If the participant and caregiver are unable/unwilling to work with the eCOA system to complete the ePROs, participant or caregiver must agree to be available to be contacted by the site to complete all eCOA activities (ePROs) via site-assisted interview at the timepoints specified in the protocol. Participants in the Safety Subset must be willing and able to work with the eCOA system to complete the eDiary.
- Participant must have at least one additional risk factor for invasive extraintestinal pathogenic Escherichia coli disease (IED), beyond a history of urinary tract infection (UTI) in the past 2 years. Additional risk factors for IED are defined as one or more of the following:
a. a history of urosepsis and/or E. coli bacteremia at any time prior to randomization, and/or
b. a history of inpatient hospitalization (for a medical/surgical cause) in the two years prior to randomization, and/or
c. presence at baseline of at least one risk factor for complicated UTI of any toxicity grade.
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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.
- Participant has a history of malignancy within 5 years before screening that does not include the following categories:(a) Participants with curatively treated 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 a 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; Participants who underwent radical prostatectomy or radiotherapy may be enrolled at the discretion of the investigator if treatment has been completed 6 months prior to the planned administration of the study vaccine (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 history of severe allergic reaction, anaphylaxis or other serious adverse reactions to vaccines or vaccines excipients (including specifically the excipients of the study vaccine; refer to IB).
- Abnormal function of the immune system resulting from:
a. Clinical conditions or their treatments expected to have an impact on the immune response elicited by the study vaccine.
b. Chronic or recurrent use of systemic corticosteroids within 3 months before administration of study vaccine and during the study. A substantially immunosuppressive steroid dose is considered to be ≥2 weeks of daily receipt of 20 mg or more of prednisone or equivalent.
c. Administration of antineoplastic and immunomodulating agents or radiotherapy expected to have an impact on the immune response elicited by the study vaccine within 6 months before administration of study vaccine and during the study.
- 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 3 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 vaccine authorized for Emergency Use Authorization, conditional Marketing Authorisation or a similar program 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 O1, O2, O4, O6, O15, O16, O18, O25, 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, excluding IED cases with microbiological confirmation from urine only, caused by ExPEC serotypes O1, O2, O4, O6, O15, O16, O18, O25, 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 O1, O2, O4, O6, O15, O16, O18, O25, and O75
•First IED event, with microbiological confirmation from blood or other sterile sites, excluding IED cases with microbiological confirmation from urine only, 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 E.coli
• First pyelonephritis event caused by any E.coli
• First UTI event caused by any E.coli
• Antibody titers to vaccine O-serotype antigens and EPA in the Immunogenicity Subset, as determined by multiplex ECL-based immunoassay and antibody titers to vaccine O-serotype antigens, as determined by 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 the hospital, including ICU hospitalization and ICU length of stay, for IED, UTI or ABP 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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 43 |
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 |
Colombia |
New Zealand |
Taiwan |
Australia |
Canada |
China |
India |
Israel |
Japan |
Korea, Republic of |
Saudi Arabia |
Thailand |
United Kingdom |
United States |
Czechia |
Denmark |
France |
Germany |
Italy |
Netherlands |
Spain |
Sweden |
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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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The end of study is considered as the last Year 3 assessment (Day
1096) for the last participant. |
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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 |