Study of a Candidate Clostridium Difficile Toxoid Vaccine in Subjects at Risk for C. Difficile Infection

Clostridium Difficile Infection Clinical Trial

Official title:

Efficacy, Immunogenicity, and Safety Study of Clostridium Difficile Toxoid Vaccine in Subjects at Risk for C. Difficile Infection (Cdiffense™)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01887912
• Other study ID #: H-030-014
• Secondary ID: 2013-000775-32U1
• Status: Terminated
• Phase: Phase 3
• Start date: July 30, 2013
• Est. completion date: June 12, 2018

Study information

• Verified date: March 2022
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of this study was to evaluate the efficacy of the Clostridium difficile vaccine to prevent primary symptomatic C. difficile infection (CDI) in participants at risk for CDI where there is a substantial unmet medical need. Primary objective: - To assess the efficacy of the C. difficile vaccine in preventing the onset of symptomatic primary CDI confirmed by polymerase chain reaction (PCR) in adult participants aged >= 50 years who are at risk for CDI and have received at least 1 injection. Secondary Objectives: Efficacy: - To assess prevention of symptomatic PCR-confirmed primary CDI cases after 3 injections administered at 0, 7, and 30 days. - To assess prevention of symptomatic PCR-confirmed primary CDI cases after completion of at least 2 injections. Immunogenicity: - To describe the immunogenicity to toxin A and toxin B at specific time points in a subset of participant and in participants with CDI at Day 0 and Day 60. Safety: - To describe the safety profile of all participants who received at least 1 injection.

Description:

The study was designed as an event-driven group sequential protocol with 4 interim analyses at defined information milestones and a final analysis when a specific number of clinical endpoints are reached. Analyses of trial futility (non-efficacy) were to be performed at the first 2 interim analyses, and the study was to be stopped if either of those analyses provided robust and compelling evidence that meaningful levels of vaccine efficacy (VE) would not be demonstrated. Following completion of the first interim analysis (50 cases of confirmed CDI observed), the futility criterion was met and in accordance with IDMC recommendation, enrollment and further vaccination ceased in November 2017. Due to the early termination of the study, some of the planned secondary efficacy endpoints could not be analyzed as all planned data were not collected. Participants were randomized to receive either the candidate vaccine or a placebo that was to be administered in a 3-dose schedule. At the time of group assignment, 928 participants (10% of total enrollment) were randomized to an immunogenicity subset; and 1859 participants (20% of total enrollment) were randomized to a reactogenicity subset. Safety was assessed in all participants in terms of unsolicited adverse events from Day 0 to Day 60, as well as serious adverse events (SAEs) throughout the study. Solicited adverse reactions were collected for 6 days following each injection in the reactogenicity subset.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 9302
• Est. completion date: June 12, 2018
• Est. primary completion date: June 12, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

• Aged >= 50 years on the day of inclusion
• Informed consent form had been signed and dated.
• Attended all scheduled visits and complied with all trial procedures.
• Covered by health insurance (if required).
• Must fulfill at least 1 of the following criteria

Risk Stratum 1:

• Had at least 2 hospital stays, each lasting at least >= 24 hours, in the 12 months before enrollment, and
• Had received systemic (not topical) antibiotics in the 12 months before enrollment, or

Risk Stratum 2:

• Was anticipated to have an in-patient hospitalization for a planned surgical procedure within 60 days of enrollment. The impending hospital stay was 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.

Exclusion Criteria:

• Participant was pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing 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).
• 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.
• 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.
• Previous vaccination against C. difficile with either the trial vaccine, another vaccine, or monoclonal antibodies.
• Diarrhea on day of enrollment.
• Self-reported current or prior CDI episode.
• Anticipated or current receipt of kidney dialysis treatment.
• History of gastrointestinal surgery for gastrointestinal malignancy (Note:

Colonoscopy, polypectomy, and appendectomy are not exclusion criteria).

• 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.
• Receiving enteral feeding (e.g., nasogastric, gastrostomy, and jejunostomy tube feeding).
• 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).
• Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine used in the trial or to a vaccine containing any of the same substances.
• Self-reported thrombocytopenia, contraindicating intramuscular vaccination.
• Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
• Current alcohol abuse or drug addiction that might interfere with the ability to comply with trial procedures in the opinion of the Investigator.
• Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion.
• Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature >= 38.0 degree Celsius [>= 100.4°Fahrenheit]). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided.
• 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.

Related Conditions & MeSH terms

• Clostridium Difficile Infection
• Clostridium Infections
• Communicable Diseases
• Infections

Intervention

Biological:
• C. difficile Toxoid Vaccine
0.5 mL, Intramuscular
• Placebo: 0.9% normal saline
0.5 mL, Intramuscular

Locations

Country	Name	City	State
Australia	Investigational Site 404	Bedford Park	South Australia
Australia	Investigational Site 401	Cairns	Queensland
Australia	Investigational Site 403	Clayton	Victoria
Canada	Investigational Site 152	Québec	Quebec
Canada	Investigational Site 151	Sherbrooke	Quebec
Canada	Investigational Site 156	Surrey	British Columbia
Canada	Investigational Site 161	Trois-Rivières	Quebec
Canada	Investigational Site 163	Truro	Nova Scotia
Canada	Investigational Site 158	Vancouver	British Columbia
Denmark	Investigational Site 215	Aarhus
Dominican Republic	Investigational Site 347	Santo Domingo
Finland	Investigational Site 203	Järvenpää
Finland	Investigational Site 201	Tampere
Finland	Investigational Site 202	Turku
France	Investigational Site 230	Dijon
France	Investigational Site 221	Paris
France	Investigational Site 229	Pringy
France	Investigational Site 223	St Priest en Jarez
France	Investigational Site 232	Tours
Germany	Investigational Site 244	Deggingen	BW
Germany	Investigational Site 245	Hamburg
Germany	Investigational Site 247	Hamburg
Germany	Investigational Site 242	Wurzburg	Bayern
Japan	Investigational Site 450	Aichi
Japan	Investigational Site 468	Chiba
Japan	Investigational Site 467	Fukui
Japan	Investigational Site 464	Fukuoka
Japan	Investigational Site 465	Fukuoka
Japan	Investigational Site 466	Fukuoka
Japan	Investigational Site 457	Gunma
Japan	Investigational Site 455	Hyogo
Japan	Investigational Site 453	Ibaraki
Japan	Investigational Site 454	Kyoto
Japan	Investigational Site 460	Kyoto
Japan	Investigational Site 452	Nagano
Japan	Investigational Site 456	Nagano
Japan	Investigational Site 458	Nagano
Japan	Investigational Site 469	Okinawa
Japan	Investigational Site 461	Osaka
Japan	Investigational Site 459	Saitama
Japan	Investigational Site 467	Shimonoseki
Japan	Investigational Site 451	Tokyo
Japan	Investigational Site 463	Yamaguchi
Korea, Republic of	Investigational Site 413	Ansan	Gyeonggi-do
Korea, Republic of	Investigational Site 446	Busan
Korea, Republic of	Investigational Site 439	Gyeonggi-do
Korea, Republic of	Investigational Site 412	Incheon
Korea, Republic of	Investigational Site 427	Incheon	Namdong-gu
Korea, Republic of	Investigational Site 408	Seoul
Korea, Republic of	Investigational Site 409	Seoul
Korea, Republic of	Investigational Site 411	Seoul
Korea, Republic of	Investigational Site 415	Seoul
Korea, Republic of	Investigational Site 418	Seoul
Korea, Republic of	Investigational Site 437	Seoul
Korea, Republic of	Investigational Site 438	Seoul
Korea, Republic of	Investigational Site 407	Wonju	Gangwon-do
Mexico	Investigational Site 363	Ciudad Victoria	Tamaulipas
Mexico	Investigational Site 351	Cuernavaca	Morelos
Mexico	Investigational Site 326	Durango
Mexico	Investigational Site 352	Ecatepec	Estado De Mexico
Mexico	Investigational Site 324	Guadalajara	Jalisco
Mexico	Investigational Site 325	Mexico City	D.f.
Mexico	Investigational Site 329	Mexico City	D.f.
Panama	Investigational Site 354	Panama City
Peru	Investigational Site 332	Jesus Maria	Lima
Peru	Investigational Site 355	Lima
Peru	Investigational Site 356	Lima
Peru	Investigational Site 365	Piura
Peru	Investigational Site 334	San Martín de Porres	Lima
Peru	Investigational Site 364	Trujillo	La Libertad
Poland	Investigational Site 284	Bydgoszcz
Poland	Investigational Site 283	Nowy Duninów
Puerto Rico	Investigational Site 171	Bayamon
Singapore	Investigational Site 419	Singapore
Singapore	Investigational Site 428	Singapore
Singapore	Investigational Site 445	Singapore
Spain	Investigational Site 294	Cordoba
Spain	Investigational Site 293	Santander
Spain	Investigational Site 292	Terrassa
Spain	Investigational Site 295	Vigo
Taiwan	Investigational Site 426	New Taipei City
Taiwan	Investigational Site 429	Taichung City
Taiwan	Investigational Site 421	Tainan
Taiwan	Investigational Site 425	Taipei
Thailand	Investigational Site 442	Bangkok
Thailand	Investigational Site 443	Bangkok
Thailand	Investigational Site 441	Khon Kaen
United Kingdom	Investigational Site 276	Blackpool
United Kingdom	Investigational Site 277	Coventry
United Kingdom	Investigational Site 281	Leeds
United Kingdom	Investigational Site 271	London
United Kingdom	Investigational Site 275	Penzance
United States	Investigational Site 190	Ann Arbor	Michigan
United States	Investigational Site 146	Asheville	North Carolina
United States	Investigational Site 149	Augusta	Georgia
United States	Investigational Site 544	Austin	Texas
United States	Investigational Site 002	Boston	Massachusetts
United States	Investigational Site 143	Bradenton	Florida
United States	Investigational Site 187	Brandon	Florida
United States	Investigational Site 013	Bronx	New York
United States	Investigational Site 528	Camp Hill	Pennsylvania
United States	Investigational Site 523	Canton	Ohio
United States	Investigational Site 540	Charleston	South Carolina
United States	Investigational Site 075	Clearwater	Florida
United States	Investigational Site 517	Clearwater	Florida
United States	Investigational Site 129	Cleveland	Ohio
United States	Investigational Site 003	Columbus	Ohio
United States	Investigational Site 055	Crystal River	Florida
United States	Investigational Site 006	Dallas	Texas
United States	Investigational Site 061	Dayton	Ohio
United States	Investigational Site 529	Decatur	Georgia
United States	Investigational Site 175	Detroit	Michigan
United States	Investigational Site 022	Endwell	New York
United States	Investigational Site 031	Fargo	North Dakota
United States	Investigational Site 183	Flint	Michigan
United States	Investigational Site 119	Fort Worth	Texas
United States	Investigational Site 506	Gainesville	Florida
United States	Investigational Site 099	Hialeah	Florida
United States	Investigational Site 189	Hillsborough	New Jersey
United States	Investigational Site 049	Idaho Falls	Idaho
United States	Investigational Site 101	Iowa City	Iowa
United States	Investigational Site 009	Jacksonville	Florida
United States	Investigational Site 051	Los Angeles	California
United States	Investigational Site 534	Los Angeles	California
United States	Investigational Site 012	Lynchburg	Virginia
United States	Investigational Site 030	Marshfield	Wisconsin
United States	Investigational Site 091	Metairie	Louisiana
United States	Investigational Site 095	Middletown	Ohio
United States	Investigational Site 104	Mobile	Alabama
United States	Investigational Site 047	Mount Pleasant	South Carolina
United States	Investigational Site 044	Neptune	New Jersey
United States	Investigational Site 084	New Orleans	Louisiana
United States	Investigational Site 135	Orem	Utah
United States	Investigational Site 050	Pawtucket	Rhode Island
United States	Investigational Site 112	Pensacola	Florida
United States	Investigational Site 194	Phoenix	Arizona
United States	Investigational Site 543	Pocatello	Idaho
United States	Investigational Site 086	Rapid City	South Dakota
United States	Investigational Site 069	Royal Oak	Michigan
United States	Investigational Site 040	Saint Petersburg	Florida
United States	Investigational Site 114	Saint Petersburg	Florida
United States	Investigational Site 080	Salt Lake City	Utah
United States	Investigational Site 193	San Antonio	Texas
United States	Investigational Site 088	Sarasota	Florida
United States	Investigational Site 010	Savannah	Georgia
United States	Investigational Site 077	Shreveport	Louisiana
United States	Investigational Site 504	Simi Valley	California
United States	Investigational Site 180	Spartanburg	South Carolina
United States	Investigational Site 057	Stanford	California
United States	Investigational Site 503	Surprise	Arizona
United States	Investigational Site 083	Uniontown	Pennsylvania
United States	Investigational Site 176	Upland	California
United States	Investigational Site 035	West Roxbury	Massachusetts
United States	Investigational Site 546	Wheat Ridge	Colorado
United States	Investigational Site 020	Wilkes-Barre	Pennsylvania
United States	Investigational Site 196	Winchester	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi Pasteur, a Sanofi Company

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Colombia,  Costa Rica,  Denmark,  Dominican Republic,  Finland,  France,  Germany,  Guatemala,  Japan,  Korea, Republic of,  Mexico,  Panama,  Peru,  Philippines,  Poland,  Puerto Rico,  Singapore,  Spain,  Sweden,  Taiwan,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Symptomatic Polymerase Chain Reaction (PCR)-Confirmed Primary C. Difficile Infection (CDI) Cases	Symptomatic PCR-confirmed CDI cases were defined as the number of participants with combination of clinical and laboratory findings. Clinical components were: >= 3 loose stools in <= 24 hours, loose stools (defined as type 6 [fluffy pieces with ragged edges, mushy] or type 7 [watery, no solid pieces] according to the Bristol Stool Chart) lasting >= 24 hours. Laboratory findings were: stool sample positive for C. difficile Toxin B by PCR at central laboratory or diagnosis of pseudomembranous colitis visualized at colonoscopy.	Up to 3 years post injection 1
Secondary	Number of Participants With Severe PCR-Confirmed Primary CDI Cases	Severe CDI cases were defined as number of participants with at least one of the following symptoms: fever >= 38.5 degree Celsius (°C), white blood cell count >= 15,000 cells/mm^3, ileus, pseudomembranous colitis, serum albumin <3 gram per deciliter, abdominal distension, abdominal tenderness, or admission to the intensive care unit within 7 days of CDI diagnosis.	Up to 3 years post injection 1
Secondary	Number of Participants With Loose Stool Episodes	Loose stools were defined as type 6 (fluffy pieces with ragged edges, mushy) or type 7 (watery, no solid pieces) according to the Bristol Stool Chart. In this outcome measure, participants with number of loose stool episodes (categorized as: loose stool episodes less than 3, 3 to 6, 7 to 10, 11 to 15 and greater than 15) were reported.	Up to 3 years post injection 1
Secondary	Number of Participants With Symptomatic PCR Confirmed CDI Cases: Per-Protocol Population	Symptomatic PCR confirmed CDI cases were defined as the number of participants with combination of clinical and laboratory findings. Clinical components were: >= 3 loose stools in <= 24 hours, loose stools (defined as type 6 [fluffy pieces with ragged edges, mushy] or type 7 [watery, no solid pieces] according to the Bristol Stool Chart) lasting >= 24 hours. Laboratory findings were: stool sample positive for C. difficile Toxin B by PCR at central laboratory or diagnosis of pseudomembranous colitis visualized at colonoscopy. Analysis was performed on per-protocol efficacy analysis set (PPEAS).	Up to 3 years post injection 1
Secondary	Serum Antibody Concentrations Against Toxins A and B Measured by Enzyme-Linked Immunosorbent Assay (ELISA)	Serum antibody concentrations against toxins A and B were measured by ELISA and expressed as geometric mean concentration (GMC). The 2-sided 95% Confidence Interval (CI) of GMC was based on the Student t-distribution. Analysis was performed on Per Protocol Immunogenicity Analysis Set, which included participants who had at least 1 injection, no relevant protocol deviations (not met inclusion criteria/ met exclusion criteria, not received vaccine/ not received in proper time window, received different vaccine than randomized, preparation and/ or administration of vaccine not per protocol, protocol-restricted therapy, not provided post-dose serology sample/serology sample did not produced a valid test result).	Day 0, Day 14, Day 30, Day 60, Day 210, Day 390, Day 570, Day 750, Day 930, and Day 1110
Secondary	Percentage of Participants With >= 2 and 4-Fold Rise in Serum Antibody Concentrations From Baseline Against Toxins A and B Measured by ELISA	Percentage of Participants with >= 2 and 4-fold rise in serum antibody concentrations against toxins A and B were measured by ELISA. The 2-sided 95% Cl of the percentage was based on Exact method calculations.	Day 60
Secondary	Serum Antibody Concentrations Against Toxins A and B Measured by ELISA in Participants With CDI	Serum antibody concentrations against toxins A and B were measured by ELISA and expressed as GMC. The 2-sided 95% CI GMC was based on the Student t-distribution. Symptomatic PCR-confirmed CDI cases were defined as the number of participants with combination of clinical and laboratory findings. Clinical components were: >= 3 loose stools in <= 24 hours, loose stools (defined as type 6 [fluffy pieces with ragged edges, mushy] or type 7 [watery, no solid pieces] according to the Bristol Stool Chart) lasting >= 24 hours. Laboratory findings were: stool sample positive for C. difficile Toxin B by PCR at central laboratory or diagnosis of pseudomembranous colitis visualized at colonoscopy.	Day 0 and Day 60
Secondary	Serum Antibody Concentrations Against Toxins A and B Measured by Toxin Neutralization Assay (TNA)	Serum antibody concentrations against toxins A and B were measured by TNA and expressed as geometric mean titer (GMT). The 2-sided 95% Cl of GMT was based on the Student t-distribution.	Day 0, Day 14, Day 30, Day 60, Day 210, Day 390, Day 570, Day 750, Day 930, and Day 1110
Secondary	Percentage of Participants With >= 2 and 4-Fold Rise in Serum Antibody Concentrations From Baseline Against Toxins A and B Measured by TNA	Percentage of Participants with >= 2 and 4-fold rise in serum antibody concentrations against toxins A and B were measured by TNA. The 2-sided 95% CI of the percentage was based on Exact method calculations.	Day 60
Secondary	Serum Antibody Concentrations Against Toxins A and B Measured by TNA in Participants With CDI	Serum antibody concentrations against toxins A and B were measured by TNA and were expressed as GMT. The 2-sided 95% CI GMC was based on the Student t-distribution. Symptomatic PCR confirmed CDI cases were defined as the number of participants with combination of clinical and laboratory findings. Clinical components were: >= 3 loose stools in <= 24 hours, loose stools (defined as type 6 [fluffy pieces with ragged edges, mushy] or type 7 [watery, no solid pieces] according to the Bristol Stool Chart) lasting >= 24 hours. Laboratory findings were: stool sample positive for C. difficile Toxin B by PCR at central laboratory or diagnosis of pseudomembranous colitis visualized at colonoscopy.	Day 0 and Day 60
Secondary	Percentage of Participants Reporting Solicited Injection Site and Systemic Reactions	Solicited injection site reactions: pain, erythema, and swelling. Pain: Grade 1: no interference with activity, Grade 2: some interference with activity, Grade 3: significant; prevents daily activity; Erythema and swelling: Grade 1: >= 25 to <=50 mm, Grade 2: >51 to <=100 mm, Grade 3: >100 mm. Solicited systemic reactions: fever, headache, malaise, myalgia, and arthralgia. Fever: Grade 1: >= 38.0°C to <=38.4°C or >= 100.4° Fahrenheit (F) to <=101.1°F, Grade 2: >=38.5°C to <= 38.9°C or >=101.2°F to <=102.0°F, Grade 3: >=39.0°C or >=102.1°F. Headache, malaise, and myalgia: Grade 1: no interference with activity, Grade 2: some interference with activity, Grade 3: significant; prevents daily activity; Arthralgia: Grade 1: free range of motion but complains of pain or discomfort, Grade 2: decreased range of motion due to pain or discomfort, Grade 3: unwilling to move due to pain.	Day 0 to Day 6 after any vaccination