E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of primary Clostridium difficile infection |
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E.1.1.1 | Medical condition in easily understood language |
Prevention of bacterial infection caused by the organism Clostridium difficile |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
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 assess the efficacy of the C. difficile vaccine in preventing the onset of symptomatic primary C. difficile infection (CDI) confirmed by polymerase chain reaction (PCR) in adult subjects aged ≥ 50 years who are at risk for CDI and have received at least 1 injection |
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E.2.2 | Secondary objectives of the trial |
Efficacy: To assess:
•Prevention of symptomatic PCR-confirmed primary CDI cases (SPCR-CPCDIC) after 3 injections (inj) administered at 0, 7 and 30 days (D)
•Prevention of SPCR-CPCDIC after completion of at least 2 inj
•Durability of prevention of SPCR-CPCDIC up to 3.0 years (Y) after the 3rd inj
•Prevention of severe primary CDI cases in subjects with PCR-confirmed primary CDI
•Effect of the vaccine on reduction of loose stool frequency in subjects who are SPCR-CPCDIC
•Effect of the vaccine on reduction of CDI episode/illness duration in subjects who are SPCR-CPCDIC
Immunogenicity: To describe the immunogenicity to toxin A and toxin B in the subset (1650 out of 16500) of subjects and in subjects with CDI (250) at Day 0 and Day 60 and in the subset (1650 out of 16500) of subjects at Day 14, Day 30 and every 6 months up to 3.0 years after the third injection.
Safety: To describe the safety profile of all subjects who receive at least 1 inj |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
An individual must fulfill all of the following criteria in order to be eligible for trial enrollment:
1) Aged ≥ 50 years on the day of inclusion
2) Informed consent form has been signed and dated
3) Able to attend all scheduled visits and to comply with all trial procedures
4) Covered by health insurance (only valid for specific countries)
5) Must fulfill at least 1 of the following criteria
Risk Stratum 1:
• Has had at least 2 hospital stays, each lasting at least ≥ 24 hours, in the 12 months before enrollment
and
• Has received systemic (not topical) antibiotics in the 12 months before enrollment
or
Risk Stratum 2:
• Is anticipated to have an in-patient hospitalization for a planned surgical procedure within 60 days of enrollment. The impending hospital stay is planned to be ≥ 72 hours for a surgery involving 1 of the following:
- Kidney/bladder/urinary system
- Musculoskeletal system
- Respiratory system
- Circulatory system
- Central nervous system
• If an individual is either an in-patient in the hospital or had a previous hospitalization, the enrollment date must be at least 30 days from hospital discharge.
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E.4 | Principal exclusion criteria |
An individual fulfilling any of the following criteria is to be excluded from trial enrollment:
1) Subject is pregnant, or lactating, or of childbearing potential (to be considered of nonchildbearing potential, a female must be post-menopausal for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination and until at least 4 weeks after the last vaccination)
2) Participation in the 4 weeks preceding the first trial vaccination or participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure
3) Receipt of any vaccine in the 4 weeks preceding the first trial vaccination except for influenza (seasonal or pandemic) and pneumococcal vaccines. This exception includes monovalent pandemic influenza vaccines and multivalent influenza vaccines
4) Previous vaccination against C. difficile with either the trial vaccine, another vaccine, or monoclonal antibodies
5) Diarrhea on day of enrollment
6) Self-reported current or prior CDI episode
7) Anticipated or current receipt of kidney dialysis treatment
8) History of gastrointestinal surgery for gastrointestinal malignancy (Note: Colonoscopy, polypectomy, and appendectomy are not exclusion criteria.)
9) History of inflammatory bowel disease, irritable bowel syndrome (must include diarrhea as a symptom), colostomy, or small or large intestine bowel surgery where resection was performed
10) Receiving enteral feeding (e.g., nasogastric, gastrostomy, and jejunostomy tube feeding)
11) Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months)
12) Known systemic hypersensitivity to any of the vaccine components, or history of a lifethreatening reaction to the vaccine used in the trial or to a vaccine containing any of the same substances
13) Self-reported thrombocytopenia, contraindicating IM vaccination
14) Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily
15) Current alcohol abuse or drug addiction that might interfere with the ability to comply with trial procedures in the opinion of the Investigator
16) Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion
17) Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]). A prospective subject should not be included in the study until the condition has resolved or the febrile event has subsided
18) Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study
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E.5 End points |
E.5.1 | Primary end point(s) |
Symptomatic PCR-confirmed primary CDI cases, defined as:
• Presence of both of the following clinical symptoms:
- ≥ 3 loose stools in ≤ 24-hours
- loose stools lasting ≥ 24 hours
and
• Stool sample positive for C. difficile by PCR
or
• Confirmatory test of pseudomembranous colitis diagnosed through colonoscopy, and, if available, provision of a stool sample for PCR testing |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
All subjects will be followed actively for efficacy (the primary occurrence or recurrence of a CDI) from Day 0 through the follow-up period for occurrence of repeated episodes of loose stools and provision of a stool sample. Some subjects may be followed for a shorter period of time if the trial is completed and the subject has not reached their maximum follow-up period.
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E.5.2 | Secondary end point(s) |
Efficacy:
• The number of symptomatic PCR-confirmed primary CDI cases after 3 injections (the per-protocol population)
• The number of symptomatic PCR-confirmed primary CDI cases after at least 2 injections
• The number of symptomatic PCR-confirmed primary CDI cases after 3 injections as a function of time since enrollment and within 3.0 years after the third injection
• The number of severe PCR-confirmed primary CDI cases. A severe CDI case is defined when a subject has 1 or more of the following: fever ≥ 38.5°C, white blood cell count ≥ 15,000 cells/mm3 (if available), ileus, pseudomembranous colitis, serum albumin <3 g/dl, abdominal distension, abdominal tenderness, or admission to the intensive care unit within 7 days of CDI diagnosis.
• The maximum number of loose stools per day associated with a symptomatic PCR-confirmed primary CDI case
• The CDI episode/illness duration associated with a symptomatic PCRconfirmed primary CDI case. Duration is calculated as (clinical cure date – clinical case date + 1)
Immunogenicity:
• Serum antibody concentrations against toxins A and B, measured by enzyme-linked immunosorbent assays (ELISA)
• Serum antibody titers against toxins A and B, measured by toxin neutralization assay (TNA)
• Exploratory assays may be performed
Safety:
1) Occurrence, nature (MedDRA preferred term), duration, intensity, and relationship to vaccination of any unsolicited systemic adverse events (AEs) reported in the 30 minutes after vaccination
2) Occurrence, time to onset, number of days of occurrence, intensity, action taken, and whether the reaction led to early termination from the study, of solicited (prelisted in the subject’s diary card and eCRF) injection site reactions occurring up to 6 days after vaccination in subjects in the reactogenicity subset
3) Occurrence, time to onset, number of days of occurrence, intensity, action taken, and whether the reaction led to early termination from the study, of solicited (prelisted in the subject’s diary card and eCRF) systemic reactions occurring up to 6 days after vaccination in subjects in the reactogenicity subset
4) Occurrence, nature (MedDRA preferred term), time to onset, duration, intensity, action taken, relationship to vaccination (for systemic AEs only), and whether the event led to early termination from the study, of unsolicited AEs up to 30 days after vaccination
5) Occurrence, nature (MedDRA preferred term), time to onset, duration, seriousness criteria, relationship to vaccination, outcome, and whether the SAE led to early termination from the study, of SAEs through 6 months after the last injection
6) Occurrence, nature (MedDRA preferred term), time to onset, duration, seriousness criteria, outcome, and whether the SAE led to early termination from the study, of SAEs considered related to vaccination and/or study procedures 6 months after the last injection through the end of the follow-up period
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood sampling:
All subjects will provide a pre-vaccination blood sample at Day (D)0 and
at D60. An immunogenicity subset (1,650 /16,500 subjects enrolled)
will provide additional blood samples at D14, pre-vaccination on D30, and every 6 months during the follow-up period.
Safety:
For subjects in the reactogenicity subset (3,300 / 16,500 subjects enrolled), solicited reactions will be recorded for 6 D after each injection.
All subjects will record information about unsolicited AEs through 30 days after the last injection. All SAEs (related and unrelated) will be collected in all subjects from Day 0 through the end of the follow-up period.
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
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 |
Brazil |
Canada |
Chile |
Colombia |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Korea, Republic of |
Mexico |
Peru |
Poland |
Romania |
Singapore |
Spain |
Sweden |
Taiwan |
United Kingdom |
United States |
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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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Last Contact Last Subject.
Main population: 4 visits (D0, D7, D30 and D60), contact at D210 then contact every 2 weeks.
Immunogenicity subset: 5 visits (D0, D7, D14, D30 and D60), then every 6 months for a maximum of 3 years (visits 6, 7, 8, 9, 10). |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 1 |