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

NCT ID: NCT01887912

Last Updated: 2022-03-28

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 9302 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-07-30
• Study Completion Date: 2018-06-12

Brief 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.

Detailed 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.

Conditions

Clostridium Difficile Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

C. difficile Vaccine Group

Participants received 1 injection of 0.5 mL C. difficile toxoid vaccine at Days 0 (Injection 1), 7 (Injection 2), and 30 (Injection 3).

Group Type: EXPERIMENTAL

C. difficile Toxoid Vaccine

Intervention Type: BIOLOGICAL

0.5 mL, Intramuscular

Placebo Group

Participants received 1 injection of 0.5 mL placebo matched to vaccine at Days 0 (Injection 1), 7 (Injection 2), and 30 (Injection 3).

Group Type: PLACEBO_COMPARATOR

Placebo: 0.9% normal saline

Intervention Type: BIOLOGICAL

0.5 mL, Intramuscular

Interventions

C. difficile Toxoid Vaccine

0.5 mL, Intramuscular

Intervention Type: BIOLOGICAL

Placebo: 0.9% normal saline

0.5 mL, Intramuscular

Intervention Type: BIOLOGICAL

Eligibility Criteria

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 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.

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Sanofi Pasteur, a Sanofi Company

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Sanofi Pasteur Inc.

Locations

Huntsville, Alabama, United States

Investigational Site 104

Mobile, Alabama, United States

Flagstaff, Arizona, United States

Investigational Site 194

Phoenix, Arizona, United States

Investigational Site 503

Surprise, Arizona, United States

Little Rock, Arkansas, United States

Bakersfield, California, United States

Banning, California, United States

Garden Grove, California, United States

La Mesa, California, United States

Investigational Site 534

Los Angeles, California, United States

Investigational Site 051

Los Angeles, California, United States

Modesto, California, United States

Redding, California, United States

Sacramento, California, United States

Investigational Site 504

Simi Valley, California, United States

Investigational Site 057

Stanford, California, United States

Investigational Site 176

Upland, California, United States

Ventura, California, United States

Investigational Site 546

Wheat Ridge, Colorado, United States

Bristol, Connecticut, United States

Danbury, Connecticut, United States

Investigational Site 143

Bradenton, Florida, United States

Investigational Site 187

Brandon, Florida, United States

Investigational Site 075

Clearwater, Florida, United States

Investigational Site 517

Clearwater, Florida, United States

Investigational Site 055

Crystal River, Florida, United States

DeLand, Florida, United States

Investigational Site 506

Gainesville, Florida, United States

Investigational Site 099

Hialeah, Florida, United States

Investigational Site 009

Jacksonville, Florida, United States

Lauderdale Lakes, Florida, United States

Miami, Florida, United States

Orange Park, Florida, United States

Investigational Site 112

Pensacola, Florida, United States

Port Saint Lucie, Florida, United States

Investigational Site 088

Sarasota, Florida, United States

Investigational Site 040

St. Petersburg, Florida, United States

Investigational Site 114

St. Petersburg, Florida, United States

Tamarac, Florida, United States

Tampa, Florida, United States

West Palm Beach, Florida, United States

Investigational Site 149

Augusta, Georgia, United States

Investigational Site 529

Decatur, Georgia, United States

Macon, Georgia, United States

Investigational Site 010

Savannah, Georgia, United States

Investigational Site 049

Idaho Falls, Idaho, United States

Investigational Site 543

Pocatello, Idaho, United States

Evanston, Illinois, United States

Peoria, Illinois, United States

Peoria, Illinois, United States

Anderson, Indiana, United States

Investigational Site 101

Iowa City, Iowa, United States

Topeka, Kansas, United States

Louisville, Kentucky, United States

Investigational Site 091

Metairie, Louisiana, United States

Investigational Site 084

New Orleans, Louisiana, United States

Opelousas, Louisiana, United States

Investigational Site 077

Shreveport, Louisiana, United States

Auburn, Maine, United States

Baltimore, Maryland, United States

Investigational Site 002

Boston, Massachusetts, United States

Investigational Site 035

West Roxbury, Massachusetts, United States

Investigational Site 190

Ann Arbor, Michigan, United States

Investigational Site 175

Detroit, Michigan, United States

Investigational Site 183

Flint, Michigan, United States

Grosse Pointe Woods, Michigan, United States

Kalamazoo, Michigan, United States

Livonia, Michigan, United States

Investigational Site 069

Royal Oak, Michigan, United States

Stevensville, Michigan, United States

Troy, Michigan, United States

Butte, Montana, United States

Investigational Site 189

Hillsborough, New Jersey, United States

Investigational Site 044

Neptune City, New Jersey, United States

Teaneck, New Jersey, United States

Albuquerque, New Mexico, United States

Albuquerque, New Mexico, United States

Investigational Site 022

Endwell, New York, United States

Rochester, New York, United States

Rochester, New York, United States

Syracuse, New York, United States

The Bronx, New York, United States

Investigational Site 013

The Bronx, New York, United States

Investigational Site 146

Asheville, North Carolina, United States

Cary, North Carolina, United States

Charlotte, North Carolina, United States

Hickory, North Carolina, United States

Raleigh, North Carolina, United States

Raleigh, North Carolina, United States

Statesville, North Carolina, United States

Wilmington, North Carolina, United States

Winston-Salem, North Carolina, United States

Investigational Site 031

Fargo, North Dakota, United States

Fargo, North Dakota, United States

Investigational Site 523

Canton, Ohio, United States

Cincinnati, Ohio, United States

Cleveland, Ohio, United States

Investigational Site 129

Cleveland, Ohio, United States

Cleveland, Ohio, United States

Investigational Site 003

Columbus, Ohio, United States

Investigational Site 061

Dayton, Ohio, United States

Dayton, Ohio, United States

Kettering, Ohio, United States

Marion, Ohio, United States

Investigational Site 095

Middletown, Ohio, United States

Bend, Oregon, United States

Investigational Site 528

Camp Hill, Pennsylvania, United States

Hershey, Pennsylvania, United States

Philadelphia, Pennsylvania, United States

Pittsburgh, Pennsylvania, United States

Pittsburgh, Pennsylvania, United States

Investigational Site 083

Uniontown, Pennsylvania, United States

West Reading, Pennsylvania, United States

Investigational Site 020

Wilkes-Barre, Pennsylvania, United States

Investigational Site 050

Pawtucket, Rhode Island, United States

Providence, Rhode Island, United States

Providence, Rhode Island, United States

Investigational Site 540

Charleston, South Carolina, United States

Investigational Site 047

Mt. Pleasant, South Carolina, United States

Investigational Site 180

Spartanburg, South Carolina, United States

Investigational Site 086

Rapid City, South Dakota, United States

Franklin, Tennessee, United States

Jackson, Tennessee, United States

Nashville, Tennessee, United States

Nashville, Tennessee, United States

Investigational Site 544

Austin, Texas, United States

Corpus Christi, Texas, United States

Investigational Site 006

Dallas, Texas, United States

Investigational Site 119

Fort Worth, Texas, United States

Groesbeck, Texas, United States

Investigational Site 193

San Antonio, Texas, United States

Tomball, Texas, United States

Investigational Site 135

Orem, Utah, United States

Investigational Site 080

Salt Lake City, Utah, United States

Investigational Site 012

Lynchburg, Virginia, United States

Williamsburg, Virginia, United States

Investigational Site 196

Winchester, Virginia, United States

Spokane, Washington, United States

Tacoma, Washington, United States

Investigational Site 030

Marshfield, Wisconsin, United States

Weston, Wisconsin, United States

Westmead, New South Wales, Australia

Investigational Site 401

Cairns, Queensland, Australia

Woolloongabba, Queensland, Australia

Investigational Site 404

Bedford Park, South Australia, Australia

Investigational Site 403

Clayton, Victoria, Australia

Nedlands, Western Australia, Australia

Subiaco, Western Australia, Australia

Salvador, Estado de Bahia, Brazil

Salvador, Estado de Bahia, Brazil

Aparecida de Goiânia, Goiás, Brazil

Belo Horizonte, Minas Gerais, Brazil

Belo Horizonte, Minas Gerais, Brazil

Juiz de Fora, Minas Gerais, Brazil

Curitiba, Paraná, Brazil

Recife, Pernambuco, Brazil

Nova Iguaçu, Rio de Janeiro, Brazil

Rio de Janeiro, Rio de Janeiro, Brazil

Natal, Rio Grande do Norte, Brazil

Canoas, Rio Grande do Sul, Brazil

Porto Alegre, Rio Grande do Sul, Brazil

Santo André, São Paulo, Brazil

Campinas, , Brazil

New Westminster, British Columbia, Canada

Investigational Site 156

Surrey, British Columbia, Canada

Investigational Site 158

Vancouver, British Columbia, Canada

Winnipeg, Manitoba, Canada

Halifax, Nova Scotia, Canada

Investigational Site 163

Truro, Nova Scotia, Canada

Guelph, Ontario, Canada

Toronto, Ontario, Canada

Montreal, Quebec, Canada

Pierrefonds, Quebec, Canada

Investigational Site 152

Québec, Quebec, Canada

Investigational Site 151

Sherbrooke, Quebec, Canada

Investigational Site 161

Trois-Rivières, Quebec, Canada

Barranquilla, Alantico, Colombia

Medellín, Antioquia, Colombia

Bogotá, Ditrito Capital, Colombia

Bogotá, Ditrito, Colombia

Armenia, Quindío Department, Colombia

Bucaramanga, Santander Department, Colombia

Floridablanca, Santander Department, Colombia

Yopal, , Colombia

San José, , Costa Rica

Investigational Site 215

Aarhus, , Denmark

Investigational Site 347

Santo Domingo, , Dominican Republic

Espoo, , Finland

Helsinki, , Finland

Helsinki, , Finland

Investigational Site 203

Järvenpää, , Finland

Kokkola, , Finland

Oulu, , Finland

Pori, , Finland

Seinäjoki, , Finland

Investigational Site 201

Tampere, , Finland

Investigational Site 202

Turku, , Finland

Vantaa, , Finland

Investigational Site 230

Dijon, , France

Lille, , France

Limoges, , France

Lyon, , France

Montpellier, , France

Orléans, , France

Investigational Site 221

Paris, , France

Investigational Site 229

Pringy, , France

Saint-Etienne, , France

Investigational Site 223

Saint-Priest-en-Jarez, , France

Tourcoing, , France

Investigational Site 232

Tours, , France

Investigational Site 244

Deggingen, Baden-Wurttemberg, Germany

Munich, Bavaria, Germany

Investigational Site 242

Würzburg, Bavaria, Germany

Cologne, North Rhine-Westphalia, Germany

Leipzig, Saxony, Germany

Jena, Thuringia, Germany

Berlin, , Germany

Berlin, , Germany

Essen, , Germany

Goch, , Germany

Investigational Site 247

Hamburg, , Germany

Investigational Site 245

Hamburg, , Germany

Leipzig, , Germany

Guatemala City, , Guatemala

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

Hyōgo, , Japan

Investigational Site 453

Ibaraki, , Japan

Investigational Site 460

Kyoto, , Japan

Investigational Site 454

Kyoto, , Japan

Investigational Site 456

Nagano, , Japan

Investigational Site 452

Nagano, , Japan

Investigational Site 458

Nagano, , Japan

Investigational Site 469

Okinawa, , Japan

Investigational Site 461

Ōsaka, , Japan

Investigational Site 459

Saitama, , Japan

Investigational Site 467

Shimonoseki, , Japan

Investigational Site 451

Tokyo, , Japan

Investigational Site 463

Yamaguchi, , Japan

Aguascalientes, Aguascalientes, Mexico

Investigational Site 325

Mexico City, D.F., Mexico

Investigational Site 329

Mexico City, D.F., Mexico

Tijuana, Estado de Baja California, Mexico

Investigational Site 324

Guadalajara, Jalisco, Mexico

Investigational Site 351

Cuernavaca, Morelos, Mexico

Monterrey, Nuevo León, Mexico

San Luis Potosí City, San Luis Potosí, Mexico

Investigational Site 352

Ecatepec de Morelos, State of Mexico, Mexico

Investigational Site 363

Ciudad Victoria, Tamaulipas, Mexico

Investigational Site 326

Durango, , Mexico

Morelos, , Mexico

San Luis Potosí City, , Mexico

Investigational Site 354

Panama City, , Panama

Investigational Site 364

Trujillo, La Libertad, Peru

Investigational Site 332

Jesus Maria, Lima region, Peru

Lima Cercado, Lima region, Peru

Investigational Site 334

San Martín de Porres, Lima region, Peru

Surquillo, Lima region, Peru

Investigational Site 356

Lima, , Peru

Investigational Site 355

Lima, , Peru

Lima, , Peru

Investigational Site 365

Piura, , Peru

Alabang, , Philippines

Dasmariñas, , Philippines

Manila, , Philippines

Manila, , Philippines

Pasig, , Philippines

Quezon City, , Philippines

Quezon City, , Philippines

Investigational Site 284

Bydgoszcz, , Poland

Investigational Site 283

Nowy Duninów, , Poland

Investigational Site 171

Bayamón, PR, Puerto Rico

Bayamón, , Puerto Rico

Singapore, , Singapore

Investigational Site 419

Singapore, , Singapore

Singapore, , Singapore

Investigational Site 428

Singapore, , Singapore

Investigational Site 445

Singapore, , Singapore

Seoul, Gangnam-gu, South Korea

Investigational Site 407

Wŏnju, Gangwon-do, South Korea

Investigational Site 413

Ansan, Gyeonggi-do, South Korea

Daegu, Jung-Gu, South Korea

Investigational Site 427

Incheon, Namdong-gu, South Korea

Seoul, Seocho-gu, South Korea

Seoul, Seodaemun-gu, South Korea

Seoul, Seongbuk-gu, South Korea

Seoul, Seongdong-gu, South Korea

Seoul, Songpa-gu, South Korea

Investigational Site 446

Busan, , South Korea

Cheongju-si, , South Korea

Investigational Site 439

Gyeonggi-do, , South Korea

Gyeonggi-do, , South Korea

Investigational Site 412

Incheon, , South Korea

Investigational Site 409

Seoul, , South Korea

Investigational Site 408

Seoul, , South Korea

Investigational Site 415

Seoul, , South Korea

Investigational Site 418

Seoul, , South Korea

Investigational Site 411

Seoul, , South Korea

Investigational Site 437

Seoul, , South Korea

Investigational Site 438

Seoul, , South Korea

Investigational Site 294

Córdoba, , Spain

Investigational Site 293

Santander, , Spain

Investigational Site 292

Terrassa, , Spain

Investigational Site 295

Vigo, , Spain

Göthenburg, SWE, Sweden

Stockholm, , Sweden

Umeå, , Sweden

Kaohsiung City, , Taiwan

Investigational Site 426

New Taipei City, , Taiwan

New Taipei City, , Taiwan

Investigational Site 429

Taichung, , Taiwan

Investigational Site 421

Tainan City, , Taiwan

Investigational Site 425

Taipei, , Taiwan

Tiachung, , Taiwan

Investigational Site 443

Bangkok, , Thailand

Investigational Site 442

Bangkok, , Thailand

Investigational Site 441

Khon Kaen, , Thailand

Investigational Site 276

Blackpool, , United Kingdom

Blackpool, , United Kingdom

Investigational Site 277

Coventry, , United Kingdom

Harrow, , United Kingdom

Investigational Site 281

Leeds, , United Kingdom

Liverpool, , United Kingdom

Investigational Site 271

London, , United Kingdom

Manchester, , United Kingdom

Middlesex, , United Kingdom

North Shields, , United Kingdom

Investigational Site 275

Penzance, , United Kingdom

Stoke-on-Trent, , United Kingdom

Countries

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

References

de Bruyn G, Gordon DL, Steiner T, Tambyah P, Cosgrove C, Martens M, Bassily E, Chan ES, Patel D, Chen J, Torre-Cisneros J, Fernando De Magalhaes Francesconi C, Gesser R, Jeanfreau R, Launay O, Laot T, Morfin-Otero R, Oviedo-Orta E, Park YS, Piazza FM, Rehm C, Rivas E, Self S, Gurunathan S. Safety, immunogenicity, and efficacy of a Clostridioides difficile toxoid vaccine candidate: a phase 3 multicentre, observer-blind, randomised, controlled trial. Lancet Infect Dis. 2021 Feb;21(2):252-262. doi: 10.1016/S1473-3099(20)30331-5. Epub 2020 Sep 15.

Reference Type: DERIVED

PMID: 32946836 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2013-000775-32

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1127-7162

Identifier Type: OTHER

Identifier Source: secondary_id

H-030-014

Identifier Type: -

Identifier Source: org_study_id