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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I, Single-center, Randomized, Observer-blind, Placebo-controlled Study to Evaluate Safety, Reactogenicity and Immunogenicity of GSK's Clostridium Difficile Investigational Vaccine Based on the F2 Antigen With or Without AS01B Adjuvant, When Administered Intramuscularly According to a 0, 1-month Schedule to Healthy Adults Aged Between 18-45 Years and Between 50-70 Years, Followed by an Additional Dose Administered in a Partial Blind Manner Within an Interval of Approximately 15 Months After Dose 2, in a Subcohort of Subjects Aged 50-70 Years

Conditions
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Clostridium Infections

Intervention / Treatment
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* Biological: C. difficile investigational vaccine based on the F2 antigen (GSK2904545A)
* Biological: C. difficile investigational vaccine based on the F2 antigen (GSK2904545A) adjuvanted with AS01B
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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. For subjects aged 50 - 70 years, Grade 3 or higher abnormal hematological, biochemical, and urinary parameters. Documentation of current or prior episode of CDI. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). Recurrent history or uncontrolled neurological disorders or seizures. Family history of congenital or hereditary immunodeficiency. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines. Acute disease and/or fever at the time of enrollment. Fever is defined as temperature ≥ 38.0°C/100.4°F. The preferred location for measuring temperature in this study will be the oral cavity. Subjects with a minor illness, without fever, may be enrolled at the discretion of the Investigator. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by physical examination or laboratory screening tests. Pregnant or lactating female. History of intestinal bleeding or history of diverticular intestinal bleeding. Surgery for gastrointestinal malignancy in the period starting 3 months prior to the first vaccination. History of chronic alcohol consumption and/or drug abuse as deemed by the Investigator to render the potential subject unable/unlikely to provide accurate safety reports. Female planning to become pregnant or planning to discontinue contraceptive precautions. Documented human immunodeficiency virus positive subject, known positivity for the surface antigen of the hepatitis B virus or known positive serologic test for the hepatitis C virus. Involvement in the planning and/or conduct of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CDIFF Ag 18 - 45 Years Group<br>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)<br>* 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.<br>* Other names: CDIFF Ag;|
| Placebo Comparator: Placebo 18 - 45 Years Group<br>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<br>* Subjects will receive 2 doses (0.5 mL each) of Placebo, administered intramuscularly in the deltoid, at a 0, 1-month dose interval.<br>|
| Experimental: CDIFF Ag 50 - 70 Years Group<br>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)<br>* 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.<br>* Other names: CDIFF Ag;|
| Experimental: CDIFF Ag + AS01B 50 - 70 Years Group<br>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<br>* 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.<br>* Other names: CDIFF Ag + AS01B;|
| Placebo Comparator: Placebo 50 - 70 Years Group<br>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<br>* Subjects will receive 2 doses (0.5 mL each) of Placebo, administered intramuscularly in the deltoid, at a 0, 1-month dose interval.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with any and Grade 3 solicited local symptoms | 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 prevents 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 (i.e. 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 | 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 (i.e. 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 (i.e. from the day of vaccination up to 29 subsequent days) after each 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. | 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 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 498 | 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 498 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum neutralizing anti-Toxin A and anti-Toxin B antibody titers, as measured by Toxin Neutralization Assay (TNA) | Serum neutralizing anti-Toxin A and anti-Toxin B antibody titers are presented as Geometric Mean Titers (GMTs), as measured by TNA. | At Day 1, Day 31, Day 61, Day 180, Day 390, Day 491, Day 521 and Day 670 | 
| Serum anti-Toxin A and anti-Toxin B antibody concentrations, as measured by Enzyme-linked immunosorbent assay (ELISA) | Serum anti-Toxin A and anti-Toxin B antibody concentrations, are presented as Geometric Mean Concentrations (GMCs), expressed in ELISA units per milliliter (EU/mL), as measured by ELISA. | At Day 1, Day 31, Day 61, Day 180, Day 390, Day 491, Day 521 and Day 670 |