Safety and Immunogenicity Study of GSK's Clostridium Difficile Vaccine 2904545A When Administered in Healthy Adults Aged 18-45 Years and 50-70 Years

NCT04026009 | Completed Phase 1 Results

• 2 other identifiers: 2081092018-002304-14
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to generate safety, reactogenicity (assessment of any expected or unexpected side effect of the vaccine) and immunogenicity (ability to induce an immune response) data for the development of a candidate Clostridium difficile (C. difficile) vaccine that would protect against primary cases of Clostridium difficile infection (CDI) and CDI recurrence. Clostridium difficile infection is a major cause of gastrointestinal illness with approximately 500,000 infections and the leading cause of gastroenteritis associated death with 29,000 deaths annually in the United States of America (USA). The emergence of extremely infectious varieties/types of C. difficile has contributed to increase the number and severity of CDI cases. In recent years, some countries (United Kingdom) have implemented hospital hygiene and other measures which resulted in significant reductions in the number of cases. The burden is, however, expected to remain significant until vaccination is available.

Conditions

Clostridium Infections

Outcome Measures

Primary Outcomes (14)

• Number of Subjects With Any and Grade 3 Solicited Local Symptoms, After Each Vaccine Dose

  Assessed solicited local symptoms are pain at injection site, redness at injection site and swelling at injection site. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = significant pain at rest, pain that pre-vents normal every day activities. Grade 3 redness/swelling = redness/swelling with a maximum diameter greater (\>) than 100 millimeters (mm).

  During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccination

• Number of Subjects With Any, Grade 3, Related and Grade 3 Related Solicited General Symptoms, After Each Vaccine Dose

  Assessed solicited general symptoms are fatigue, fever \[defined as oral temperature equal to or higher than (\>=) 38 degrees Celsius (°C)\], gastrointestinal symptoms (nausea, vomiting, diarrhea, and/or abdominal pain), headache, myalgia, shivering and arthralgia. Any = occurrence of the symptom regardless of intensity grade and relationship to vaccination. Grade 3 symptom = symptom that prevents normal, everyday activities. Grade 3 fever = oral temperature higher (\>) than 39.0°C. Related symptom = symptom assessed by the investigator as causally related to the study vaccination. Grade 3 related symptom = Grade 3 symptom assessed by the investigator as causally related to the study vaccination.

  During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccination

• Number of Subjects With Any, Grade 3, Related, Grade 3 Related and Medically Attended Unsolicited Adverse Events (AEs)

  An unsolicited AE is any adverse event reported in addition to those solicited during the clinical study. Also, any "solicited" symptom with onset outside the specified period of follow-up for solicited symptoms is reported as an unsolicited adverse event. Potential unsolicited AEs may be medically attended (defined as symptoms or illnesses requiring hospitalization, or emergency room visit, or visit to/by a health care provider) or were of concern to the subjects. Any = occurrence of the symptom regardless of intensity grade and relationship to vaccination. Grade 3 symptom = symptom that prevents normal, everyday activities. Related symptom = symptom assessed by the investigator as causally related to the study vaccination. Grade 3 related symptom = Grade 3 symptom assessed by the investigator as causally related to the study vaccination.

  During the 30-day follow-up period (from the day of vaccination up to 29 subsequent days) after any vaccination

• Number of Subjects With Serious Adverse Events (SAEs)

  An SAE is any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, represents a congenital anomaly/birth defect in the offspring of a study subject.

  From Day 1 up to and including Day 390 (Epoch 001)

• Number of Subjects With Potential Immune-mediated Diseases (pIMDs)

  pIMDs are a subset of adverse events of specific interest (AESIs) that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology.

  During the whole study period (from Day 1 up to Day 390 [for subjects receiving 2 vaccine doses] and from Day 1 up to Day 670 [for subjects receiving 3 vaccine doses])

• Number of Subjects With Hematological, Biochemical, and Urinary Laboratory Abnormalities at Screening

  Hematological (white blood cells, platelet count, hemoglobin level), biochemical (alanine aminotransferase, aspartate aminotransferase, creatinine, C-reactive protein and urate/uric acid) and urinary (protein, glucose and red blood cells) parameters are assessed. C-reactive protein is only assessed during the screening visit. Grades are based on the local laboratory normal ranges and derived from the FDA Toxicity Grading Scale for laboratory abnormalities.

  At Screening (from Day -15 up to Day -1 [for subjects receiving 2 vaccine doses] and at Day 476 [for subjects receiving 3 vaccine doses])

• Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 8

  Hematological (white blood cells, platelet count, hemoglobin level), biochemical (alanine aminotransferase, aspartate aminotransferase, creatinine and urate/uric acid) parameters are assessed. Grades are based on the local laboratory normal ranges and derived from the FDA Toxicity Grading Scale for laboratory abnormalities.

  At Day 8

• Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 31

  Hematological (white blood cells, platelet count, hemoglobin level), biochemical (alanine aminotransferase, aspartate aminotransferase, creatinine and urate/uric acid) parameters are assessed. Grades are based on the local laboratory normal ranges and derived from the FDA Toxicity Grading Scale for laboratory abnormalities.

  At Day 31

• Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 38

  Hematological (white blood cells, platelet count, hemoglobin level), biochemical (alanine aminotransferase, aspartate aminotransferase, creatinine and urate/uric acid) parameters are assessed. Grades are based on the local laboratory normal ranges and derived from the FDA Toxicity Grading Scale for laboratory abnormalities.

  At Day 38

• Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 180

  Hematological (white blood cells, platelet count, hemoglobin level), biochemical (alanine aminotransferase, aspartate aminotransferase, creatinine and urate/uric acid) parameters are assessed. Grades are based on the local laboratory normal ranges and derived from the FDA Toxicity Grading Scale for laboratory abnormalities.

  At Day 180

• Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 390

  Hematological (white blood cells, platelet count, hemoglobin level), biochemical (alanine aminotransferase, aspartate aminotransferase, creatinine and urate/uric acid) parameters are assessed. Grades are based on the local laboratory normal ranges and derived from the FDA Toxicity Grading Scale for laboratory abnormalities.

  At Day 390

• Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 476

  Hematological (white blood cells, platelet count, hemoglobin level), biochemical (alanine aminotransferase, aspartate aminotransferase, creatinine and urate/uric acid) parameters are assessed. Grades are based on the local laboratory normal ranges and derived from the FDA Toxicity Grading Scale for laboratory abnormalities.

  At Day 476

• Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 491

  Hematological (white blood cells, platelet count, hemoglobin level), biochemical (alanine aminotransferase, aspartate aminotransferase, creatinine and urate/uric acid) parameters are assessed. Grades are based on the local laboratory normal ranges and derived from the FDA Toxicity Grading Scale for laboratory abnormalities.

  At Day 491

• Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 670

  Hematological (white blood cells, platelet count, hemoglobin level), biochemical (alanine aminotransferase, aspartate aminotransferase, creatinine and urate/uric acid) parameters are assessed. Grades are based on the local laboratory normal ranges and derived from the FDA Toxicity Grading Scale for laboratory abnormalities.

  At Day 670

Secondary Outcomes (1)

• Serum Neutralizing Anti-Toxin A and Anti-Toxin B Antibody Titers, as Measured by Toxin Neutralization Assay (TNA)

  At Day 1, Day 31, Day 61, Day 180, Day 390, Day 491, Day 521 and Day 670

Study Arms (5)

CDIFF Ag 18 - 45 Years Group

EXPERIMENTAL

Healthy male and female subjects, aged between and including 18 and 45 years old, who receive CDIFF antigen (Ag) vaccine administered intramuscularly in the deltoid, according to a 0, 1-month vaccination schedule.

Biological: C. difficile investigational vaccine based on the F2 antigen (GSK2904545A)

Placebo 18 - 45 Years Group

PLACEBO COMPARATOR

Healthy male and female subjects, aged between and including 18 and 45 years old, who receive Placebo administered intramuscularly in the deltoid, according to a 0, 1-month vaccination schedule.

Drug: Placebo

CDIFF Ag 50 - 70 Years Group

EXPERIMENTAL

Healthy male and female subjects, aged between and including 50 and 70 years old, who receive CDIFF antigen (Ag) vaccine administered intramuscularly in the deltoid, according to a 0, 1-month vaccination schedule. A third dose of CDIFF Ag vaccine is to be administered to a subcohort of subjects aged 50-70 years, approximately 15 months after the administration of the second dose.

Biological: C. difficile investigational vaccine based on the F2 antigen (GSK2904545A)

CDIFF Ag + AS01B 50 - 70 Years Group

EXPERIMENTAL

Healthy male and female subjects, aged between and including 50 and 70 years old, who receive CDIFF Ag + AS01B adjuvant vaccine administered intramuscularly in the deltoid, according to a 0, 1-month vaccination schedule. A third dose of CDIFF Ag + AS01B adjuvant vaccine is to be administered to a subcohort of subjects aged 50-70 years, approximately 15 months after the administration of the second dose.

Biological: C. difficile investigational vaccine based on the F2 antigen (GSK2904545A) adjuvanted with AS01B

Placebo 50 - 70 Years Group

PLACEBO COMPARATOR

Healthy male and female subjects, aged between and including 50 and 70 years old, who receive Placebo administered intramuscularly in the deltoid, according to a 0, 1-month vaccination schedule.

Drug: Placebo

Interventions

C. difficile investigational vaccine based on the F2 antigen (GSK2904545A) BIOLOGICAL

Subjects in CDIFF Ag 18 - 45 Years and CDIFF Ag 50 - 70 Years Groups will receive 2 or 3 doses (0.5 mL each) of CDIFF Ag vaccine. The vaccine will be administered intramuscularly in the deltoid, at a 0, 1-month dose interval. The third dose will be administered approximately 15 months after the second dose.

Also known as: CDIFF Ag

CDIFF Ag 18 - 45 Years Group; CDIFF Ag 50 - 70 Years Group

C. difficile investigational vaccine based on the F2 antigen (GSK2904545A) adjuvanted with AS01B BIOLOGICAL

Subjects in CDIFF Ag + AS01B 50 - 70 Years Group will receive 2 or 3 doses (0.5 mL each) of CDIFF Ag + AS01B vaccine. The vaccine will be administered intramuscularly in the deltoid, at a 0, 1-month dose interval. The third dose will be administered approximately 15 months after the second dose.

Also known as: CDIFF Ag + AS01B

CDIFF Ag + AS01B 50 - 70 Years Group

Placebo DRUG

Subjects will receive 2 doses (0.5 mL each) of Placebo, administered intramuscularly in the deltoid, at a 0, 1-month dose interval.

Placebo 18 - 45 Years Group; Placebo 50 - 70 Years Group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects who, in the opinion of the Investigator, can and will comply with the requirements of the protocol.
• Written or witnessed/thumb print informed consent obtained from the subject prior to performance of any study specific procedure.
• For Step 1 only: A male or female between, and including, 18-45 years of age at the time of the first vaccination.
• For Steps 2, 3, and 4: A male or female between, and including, 50-70 years of age at the time of the first vaccination.
• Healthy subjects as established by medical history and clinical examination before entering into the study.
• Subjects free of any uncontrolled chronic illnesses as established by medical history and clinical examination before entering into the study.
• Female subjects of non-childbearing potential may be enrolled in the study.
• Non-childbearing potential is defined as premenarche, current bilateral tubal ligation or occlusion, hysterectomy, bilateral ovariectomy, or post-menopause.
• Female subjects of childbearing potential may be enrolled in the study, if the subject:
• Has practiced adequate contraception for 30 days prior to vaccination, and
• Has a negative urine pregnancy test on the day of vaccination, and
• Has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series.

You may not qualify if:

• Health condition that, in the opinion of the Investigator, may interfere with optimal participation in the study or place the volunteer at increased risk of AEs. Study clinicians, in consultation with the Principal Investigator will use clinical judgment on a case by case basis to assess safety risks under this criterion. The Principal Investigator will consult with the Medical Monitor as appropriate.
• Use of any investigational or nonregistered product other than the study vaccine(s) during the period starting 30 days before the first dose of study vaccine(s) (Day 29 to Day 1), or planned use during the study period.
• Any medical condition that in the judgment of the Investigator would make IM injection unsafe and subjects under treatment with anticoagulant therapy.
• Chronic administration of immunosuppressants or other immune modifying drugs during the period starting 3 months prior to the first vaccination. For corticosteroids, this will mean prednisone ≥ 5 milligrams per day (mg/day) (for adult subjects), or equivalent. Inhaled and topical steroids are allowed.
• Administration of long acting immune modifying drugs at any time during the study period.
• Administration of immunosuppressive therapy, including chemotherapeutic agents used to treat cancer or other conditions, and treatments associated with organ or bone marrow transplantation or autoimmune disease.
• Administration of immunoglobulins and/or any blood products during the period starting 3 months before the first vaccination of study treatment or planned administration during the study period.
• Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 6 weeks before the first vaccination and ending 6 weeks after the last vaccination, with the exception of inactivated influenza vaccine which can be administered up to 14 days before or from 30 days after the last study vaccination.
• In case an emergency mass vaccination for an unforeseen public health threat (eg, a pandemic) is recommended and/or organized by public health authorities outside the routine immunization program, the time period described above can be reduced if, necessary for that vaccine, provided it is used according to the local governmental recommendations and that the Sponsor is notified accordingly.
• Planned administration of GSK's Herpes Zoster vaccine marketed as Shingrix or an adjuvanted recombinant varicella zoster virus envelope gE subunit vaccine (HZ/su) within 180 days before the first dose and within 180 days after the last dose of the study vaccine.
• Planned elective surgery during the study period.
• Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product.
• Body mass index \< 19 kg/m\^2 or ≥ 35 kg/m\^2.
• Clinically relevant physical examination abnormalities.
• For subjects aged 18 - 45 years, Grade 2 or higher abnormal hematological, biochemical, and urinary parameters.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Ghent, 9000, Belgium

Location

Related Publications (1)

• Leroux-Roels I, Alhatemi A, Caubet M, De Boever F, de Wergifosse B, El Idrissi M, Ferreira GS, Jacobs B, Lambert A, Morel S, Servais C, Yarzabal JP. Safety and Immunogenicity of an Adjuvanted Clostridioides difficile Vaccine Candidate in Healthy Adults: A Randomized Placebo-Controlled Phase 1 Study. J Infect Dis. 2025 Mar 17;231(3):e511-e520. doi: 10.1093/infdis/jiae466.

  PMID: 39447053 DERIVED

MeSH Terms

Conditions

Clostridium Infections

Condition Hierarchy (Ancestors)

Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This is a randomized, observer-blind and partial blind (only for third dose) study. Given the different appearance of the C.difficile investigational vaccines and placebo, double blinding is not possible, and the study will be conducted in an observer-blind manner. In an observer-blind study, the subject, the Contract Research Organization personnel, and the study center and Sponsor personnel involved in the clinical evaluation of the subjects are blinded while other study personnel may be aware of the treatment assignment. When all data up to Day 61 are available, a statistical analysis will be performed.This analysis may lead to the unblinding of some subjects.A statistician will be unblinded for the analysis.The study will be considered as partial blind from this point onwards. The Investigator and the subjects will not have access to the treatment allocation up to Day 390. After Day 390, only the subjects will remain fully blinded, while the Investigator will be partially blinded.
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: A 4-step staggered design will be used to ensure maximum safety of the participating subjects: Step 1: Vaccination of approximately 20 subjects aged 18-45 years. Step 2: Vaccination of approximately 20 subjects aged 50-70 years. Step 3: Vaccination of approximately 30 subjects aged 50-70 years. An iSRC will review all accumulating safety data after Dose 1 and 2 in Steps 1 to 3. If considered appropriate to proceed, the next step will start. Step 4: Vaccination of approximately 70 subjects aged 50-70 years. An iSRC will review all accumulating safety data 3 weeks after the start of vaccination in Step 4 and then about every 3 weeks until all subjects have received Dose 1. In addition, the iSRC will review all safety data after Dose 2 and after that a subcohort of subjects will receive the third dose. If there are any safety concerns observed during SRT reviews post Dose 3, an ad hoc iSRC meeting will take place to review the unblinded safety data.

Study Record Dates

• First Submitted: July 16, 2019
• First Posted: July 19, 2019
• Study Start: August 5, 2019
• Primary Completion: May 10, 2022
• Study Completion: May 10, 2022
• Last Updated: September 23, 2024
• Results First Posted: September 23, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

BE (1)