Clinical trial NCT04026009: Safety and Immunogenicity Study of GSK's Clostridium Difficile Vaccine 2904545A When Administered in Healthy Adults Aged 18-45 Years and 50-70 Years
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Clostridium Infections
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2019-07-19
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: PREVENTION

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.


Eligibility criteria: Inclusion Criteria:

1. Subjects who, in the opinion of the Investigator, can and will comply with the requirements of the protocol.
2. Written or witnessed/thumb print informed consent obtained from the subject prior to performance of any study specific procedure.
3. For Step 1 only: A male or female between, and including, 18-45 years of age at the time of the first vaccination.
4. 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.
5. Healthy subjects as established by medical history and clinical examination before entering into the study.
6. Subjects free of any uncontrolled chronic illnesses as established by medical history and clinical examination before entering into the study.
7. 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:

1. 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.
2. 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.
3. Any medical condition that in the judgment of the Investigator would make IM injection unsafe and subjects under treatment with anticoagulant therapy.
4. 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.
5. Administration of long acting immune modifying drugs at any time during the study period.
6. 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.
7. 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.
8. 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.
9. 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.
10. Planned elective surgery during the study period.
11. 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.
12. Body mass index \< 19 kg/m\^2 or ≥ 35 kg/m\^2.
13. Clinically relevant physical examination abnormalities.
14. For subjects aged 18 - 45 years, Grade 2 or higher abnormal hematological, biochemical, and urinary parameters.
15. For subjects aged 50 - 70 years, Grade 3 or higher abnormal hematological, biochemical, and urinary parameters.
16. Documentation of current or prior episode of CDI.
17. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
18. Recurrent history or uncontrolled neurological disorders or seizures.
19. Family history of congenital or hereditary immunodeficiency.
20. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.
21. 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.
22. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by physical examination or laboratory screening tests.
23. Pregnant or lactating female.
24. History of intestinal bleeding or history of diverticular intestinal bleeding.
25. Surgery for gastrointestinal malignancy in the period starting 3 months prior to the first vaccination.
26. 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.
27. Female planning to become pregnant or planning to discontinue contraceptive precautions.
28. 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.
29. Involvement in the planning and/or conduct of the study.

Primary outcomes:
measure: Number of Subjects With Any and Grade 3 Solicited Local Symptoms, After Each Vaccine Dose
timeFrame: During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccination
measure: Number of Subjects With Any, Grade 3, Related and Grade 3 Related Solicited General Symptoms, After Each Vaccine Dose
timeFrame: During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccination
measure: Number of Subjects With Any, Grade 3, Related, Grade 3 Related and Medically Attended Unsolicited Adverse Events (AEs)
timeFrame: During the 30-day follow-up period (from the day of vaccination up to 29 subsequent days) after any vaccination
measure: Number of Subjects With Serious Adverse Events (SAEs)
timeFrame: From Day 1 up to and including Day 390 (Epoch 001)
measure: Number of Subjects With Potential Immune-mediated Diseases (pIMDs)
timeFrame: 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])
measure: Number of Subjects With Hematological, Biochemical, and Urinary Laboratory Abnormalities at Screening
timeFrame: 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])
measure: Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 8
timeFrame: At Day 8
measure: Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 31
timeFrame: At Day 31
measure: Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 38
timeFrame: At Day 38
measure: Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 180
timeFrame: At Day 180
measure: Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 390
timeFrame: At Day 390
measure: Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 476
timeFrame: At Day 476
measure: Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 491
timeFrame: At Day 491
measure: Number of Subjects With Hematological and Biochemical Laboratory Abnormalities at Day 670
timeFrame: At Day 670
Secondary outcomes:
measure: Serum Neutralizing Anti-Toxin A and Anti-Toxin B Antibody Titers, as Measured by Toxin Neutralization Assay (TNA)
timeFrame: At Day 1, Day 31, Day 61, Day 180, Day 390, Day 491, Day 521 and Day 670
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: