Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 25 of 37 for:    "Shigellosis"

A Study to Evaluate the Efficacy, Safety and Immunogenicity of a Vaccine Designed to Protect Against Infection With Shigella Sonnei in Healthy Adults

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03527173
Recruitment Status : Active, not recruiting
First Posted : May 17, 2018
Last Update Posted : June 14, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:

The purpose of this study is to evaluate the efficacy, safety and immunogenicity of the GSK3536852A vaccine, which was designed to protect against shigellosis caused by Shigella sonnei (S. sonnei) and is using the new Generalized Modules for Membrane Antigens (GMMA) platform technology developed by GlaxoSmithKline (GSK) Vaccines Institute for Global Health (GVGH).

The study vaccine could be the stepping stone for the development of a multivalent broadly protective Shigella vaccine for vaccination of impoverished communities where shigellosis is endemic. However, a standalone monovalent vaccine against S. sonnei could be used to protect travelers against diarrheal shigellosis, as the vast majority of travelers' shigellosis is caused by S. sonnei, and even to protect infants in endemic regions where shigellosis is primarily caused by S. sonnei.

The GSK3536852A vaccine has been tested in two Phase I dose escalation studies in Europe to assess its safety and immunogenicity via three routes of administration: intramuscular (IM), intranasal (IN) and intradermal (ID). The results from the first study (dose escalation with IM vaccination) have shown that the vaccine has an acceptable safety profile and is well-tolerated up to a dose of 100 micrograms (µg). The results from the second study (dose escalation with ID, IN and IM vaccination) showed that GSK3536852A vaccine is well-tolerated also when administered by the ID and IN routes of vaccination. However, immunogenicity data have shown that GSK3536852A vaccine administered by the ID and IN routes is not as immunogenic as GSK3536852A vaccine administered by the IM route. Therefore, it has been decided to proceed with the clinical development program of this vaccine only using the IM vaccination route. In terms of dosage, the regimen tested in Phase I studies (three doses given one month apart) did not show any significant benefit from the third dose in terms of immunogenicity, therefore a two dose schedule was selected for next studies.

A Phase IIa study, conducted in endemic regions of Africa (i.e., Kenya), has just been completed and confirmed the acceptable safety profile and immunogenicity of GSK3536852A vaccine.

Performing this vaccine-human challenge study may give the opportunity to establish evidence of clinical protection induced by the candidate S. sonnei vaccine (GSK3536852A vaccine) at an early development stage.


Condition or disease Intervention/treatment Phase
Dysentery, Bacillary Biological: GSK3536852A vaccine Drug: GAHB-Placebo Phase 2

Detailed Description:
The original study protocol has been amended due to requests from the Food and Drug Administration (FDA), requests from the funder of the study, Bill & Melinda Gates Foundation (BMGF), and to further align the protocol to other GSK studies and to the challenge model established at the Cincinnati Children's Hospital Medical Centre.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Observer-blind The subject, the site and sponsor personnel involved in the clinical evaluation of the subjects are blinded while other study personnel may be aware of the treatment assignment.
Primary Purpose: Prevention
Official Title: Efficacy, Safety and Immunogenicity of GVGH Shigella Sonnei Vaccine (1790GAHB) in a Human Challenge Study of Healthy Non-immune Adults
Actual Study Start Date : August 29, 2018
Actual Primary Completion Date : May 9, 2019
Estimated Study Completion Date : November 1, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: GSK3536852A Group
Male or female subjects between, and including, 18 and 50 years of age at the time of the first vaccination, receiving 2 doses of the GSK3536852A study vaccine at Day 1 and Day 29, intramuscularly into the upper deltoid region of the non-dominant arm. At 28 days after the second dose (Day 57), subjects will receive the challenge dose.
Biological: GSK3536852A vaccine
Subjects receiving 2 doses of study vaccine by intramuscular route, 28 days apart (Day 1 and Day 29) and a challenge dose at Day 57.

Placebo Comparator: Placebo Group
Male or female subjects between, and including, 18 and 50 years of age at the time of the first vaccination, receiving 2 doses of placebo at Day 1 and Day 29, intramuscularly into the upper deltoid region of the non-dominant arm. At 28 days after the second dose (Day 57), subjects will receive the challenge dose.
Drug: GAHB-Placebo
Subjects receiving 2 doses of GAHB-placebo by intramuscular route, 28 days apart (Day 1 and Day 29) and a challenge dose at Day 57.




Primary Outcome Measures :
  1. Number of subjects with shigellosis according to the primary case definition [ Time Frame: Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64), in all subjects. ]
    Vaccine efficacy (VE) is measured by the rate of shigellosis, fulfilling the protocol primary case definition: Shedding of S. sonnei 53G accompanied by moderate or severe diarrhea OR shedding with an oral temperature of greater than or equal to (≥) 38.5°C. Moderate diarrhea consists of 4 to 5 loose or watery (Grade 3 to 5) stools or 400 to 800 grams of Grade 3 to 5 stools within 24 hours, while severe diarrhea includes 6 or more loose or watery (Grade 3 to 5) stools or greater than (>) 800 grams of Grades 3 to 5 stools within 24 hours or required medical intervention. In case of severe diarrhea, medical intervention is defined as intravenous (IV) fluids administration or anticipation of antibiotic treatment before the 5th day after challenge. Grade 3 = viscous opaque liquid or semi-liquid which assumes the shape of the bowl; Grade 4 = watery opaque liquid; Grade 5 = clear watery or mucoid liquid.


Secondary Outcome Measures :
  1. Number of subjects with shigellosis according to Controlled Human Infection Model (CHIM) working group case definition for shigellosis [ Time Frame: During inpatient stay (from Day 57 up to Day 64) ]
    Vaccine efficacy is measured against: the rate of shigellosis fulfilling the BMGF CHIM working group case definition for shigellosis. Vaccine efficacy is also measured as shedding of S. sonnei strain 53G, severe diarrhea, more severe diarrhea, dysentery, weight of all Grade 3-5 stools, total number of all grade 3-5 stools, confirmed S. sonnei 53G shedding AND moderate or severe diarrhea OR dysentery OR presence of oral temperature ≥ 38.5°C OR presence of one or more severe intestinal symptoms (abdominal pain, cramping, nausea, vomiting, gas, and anorexia), disease not fulfilling the protocol primary case definition for shigellosis associated or not with mild to moderate symptoms, and time to onset of shigellosis after challenge according to the primary case definition.

  2. Number of subjects with shigellosis [ Time Frame: During inpatient stay (from Day 57 up to Day 64) ]
    Vaccine efficacy is measured against the following definition of shigellosis: severe diarrhea OR moderate diarrhea with fever or with one or more moderate constitutional/enteric symptom OR dysentery [[≥2 loose stools with gross blood (hemoccult positive) in 24 hours] AND [≥1 reportable constitutional/enteric symptom]].

  3. Number of subjects with more severe shigellosis [ Time Frame: During inpatient stay (from Day 57 up to Day 64) ]
    Vaccine efficacy is measured against the following definition of more severe shigellosis: severe or moderate diarrhea with fever or with one or more severe constitutional/enteric symptom OR dysentery [[≥2 loose stools with gross blood (hemoccult positive) in 24 hours] AND [≥1 severe constitutional/enteric symptom]].

  4. Number of subjects with solicited local Adverse Events (AEs) [ Time Frame: During the 7-day follow-up period (i.e., on the day of vaccination and 6 subsequent days) after each vaccine dose ]
    Solicited local AEs include: pain, erythema and induration, at injection site. Any = occurrence of local adverse event regardless of intensity grade.

  5. Number of subjects with solicited systemic Adverse Events (AEs) [ Time Frame: During the 7-day follow-up period (i.e., on the day of vaccination and 6 subsequent days) after each vaccine dose ]
    Solicited systemic AEs include: arthralgia, chills, fatigue, malaise, myalgia, fever and headache. Any = occurrence of systemic adverse event regardless of intensity grade.

  6. Number of subjects with unsolicited AEs [ Time Frame: During the 28-day follow-up period after vaccination (i.e., on the day of vaccination and 27 subsequent days) and during the 28-day follow-up period after challenge ]
    An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination.

  7. Number of subjects reporting all serious adverse events (SAEs) and related SAEs [ Time Frame: From Day 1 up to study end at Day 237 (at Day 57 + 6 Months) ]
    Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. Related SAEs = SAEs assessed by the investigator as related to the vaccination.

  8. Number of subjects with adverse events of special interest (AESI) (i.e., symptomatic neutropenia) [ Time Frame: From Day 1 up to study end at Day 237 (at Day 57 + 6 Months) ]
    AESI are predefined (serious or non-serious) AEs of scientific and medical concern specific to the product or program, for which ongoing monitoring and rapid communication by the investigator to the sponsor can be appropriate, because such an event might warrant further investigation in order to characterize and understand it.

  9. Number of subjects with hematological laboratory parameters out of range or clinically significant value(s) [ Time Frame: At Day 8 (7 days after the first vaccination), at Day 36 (7 days after the second vaccination) and at Day 237 (at Day 57 + 6 Months) ]
    Among hematological parameters assessed are: White Blood Cells [WBC], Red Blood Cells [RBC], Hemoglobin [Hgb], Hematocrit [Hct], Platelets [PLT], Eosinophils [EOS], Basophils [BSP], Neutrophils [NEU], Monocytes [MON] and Lymphocytes [LYM].

  10. IgG Geometric mean concentrations (GMCs) against anti-S. sonnei LPS antibodies after vaccination [ Time Frame: At Day 1 (pre-vaccination), at Day 8 (7 days after the first vaccination), at Day 36 (7 days after the second vaccination), at Day 29 (28 days after the first vaccination) and at Day 57 (28 days after the second vaccination) ]
    Concentrations of antibodies against S. sonnei are assessed by ELISA and measured in ELISA Units per milliliter (EU/mL).

  11. IgG Geometric mean concentrations (GMCs) against anti-S. sonnei LPS antibodies after challenge [ Time Frame: At Day 57 (pre-challenge), at Day 64 (7 days after challenge) and at Day 85 (28 days after challenge) ]
    Concentrations of antibodies against S. sonnei are assessed by ELISA and measured in EU/mL.

  12. Number of subjects achieving a post vaccination anti-S. Sonnei LPS concentration ≥ 121 EU/ml [ Time Frame: At Day 29 (28 days after the first vaccination) and at Day 57 (28 days after the second vaccination) ]
    This cut-off is based on the results of the previous Phase I study and estimated results of the median antibody titer in a panel of 87 Israeli convalescent subjects after natural infection by S. sonnei.

  13. Number of seroresponders for anti-S. sonnei LPS [ Time Frame: At Day 29 (28 days after the first vaccination) and at Day 57 (28 days after the second vaccination) ]

    Seroresponse is aimed to define a significant increase in anti-S. sonnei LPS IgG concentration in post-vaccination samples and relies on the definition already used in a previous phase II study in Kenyan population. For the purpose of this study seroresponse is defined as:

    • If the baseline value is greater than (>) 50 EU/mL then an increase of at least 50% in the post-vaccination sample as compared to baseline.
    • If the baseline value is less or equal to (≤) 50 EU/mL then an increase of at least 25 EU/mL in the post-vaccination sample as compared to baseline.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
  • Written informed consent obtained from the subject prior to performing any study specific procedure.
  • Individuals who, after the nature of the study has been explained to them, have shown adequate comprehension of the study procedures and knowledge of study.
  • A male or female between, and including, 18 and 50 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.
  • Seronegative for human immunodeficiency virus (HIV), hepatitis B and C.
  • Female subjects of non-childbearing potential may be enrolled in the study.
  • 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 pregnancy test on the day of vaccination, and
    • Has agreed to continue adequate contraception during the entire study period.

Exclusion Criteria:

  • Received an investigational or non-registered medicinal product within 30 days prior to informed consent, or planned use during the study period.
  • Any behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the subject's ability to participate in the study.
  • History of any neurological disorders or seizures.
  • Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the subject due to participation in the study.
  • Human Leukocyte Antigen (HLA)-B27 positive test at screening and/or with history of reactive arthritis.
  • Clinical conditions representing a contraindication to intramuscular vaccination and blood draws.
  • Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine/placebo dose. For corticosteroids, this will mean prednisone ≥ 20 milligrams (mg)/day, or equivalent. Inhaled except for doses > 800 µg/day and topical steroids are allowed.
  • Administration of long-acting immune-modifying drugs at any time during the study period. Subjects may be on chronic or as needed medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition.
  • Known bleeding diathesis or any condition that may be associated with a prolonged bleeding time.
  • 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.
  • History of having participated in a previous Shigella challenge study.
  • Individuals who have a previously laboratory confirmed case of disease caused by S. sonnei or serology positive for local anti S. sonnei LPS IgG Screening-ELISA at screening.
  • History of any serious chronic or progressive disease according to judgment of the investigator.
  • History of any malignancy or lymphoproliferative disorder.
  • Known to be part of study personnel or being a close family member to the personnel conducting this study.
  • History of anaphylactic reaction or allergy to vaccine/placebo or challenge agent components or any other allergies deemed by the investigator to increase the risk of an AE if they were to participate in the study.
  • Known allergy to ciprofloxacin or the other antibiotics used for treatment as deemed by the investigator.
  • Individuals receiving a course of antibiotics within a week of the challenge will be ineligible to receive the challenge strain.
  • History of gastric acid hyper-secretory disorders as assessed and judged by the investigator or any other significant intestinal disorder.
  • Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
  • Family history of congenital or hereditary immunodeficiency.
  • History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine/placebo or challenge agent.
  • Acute disease and/or fever at the time of enrolment.
  • Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests. Chronic medical diagnoses or conditions should be stable for the last 60 days. This includes no change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical diagnosis or condition in the 60 days prior to enrolment.
  • A clinically significant sign or symptoms of acute illness, significant anomalies in vital signs.
  • Known to handle food as part of work related activities.
  • Hepatomegaly, right upper quadrant abdominal pain or tenderness.
  • Received immunoglobulins or any blood products within 180 days prior to informed consent or planned administration during the study period.
  • Pregnant or lactating female.
  • Female planning to become pregnant or planning to discontinue contraceptive precautions.
  • Females with history of stillbirth, neonatal loss, or previous infant with anomaly, except those who have had a planned termination of pregnancy, hysterectomy or bilateral tubal ligation.
  • History of chronic alcohol consumption and/or drug abuse. Chronic alcohol consumption is defined as: a prolonged period of frequent, heavy alcohol use; the inability to control drinking once it has begun; physical dependence manifested by withdrawal symptoms when the individual stops using alcohol; tolerance, or the need to use more and more alcohol to achieve the same effects; a variety of social and/or legal problems arising from alcohol use.
  • Known to have close household or professional contacts with people with immunosuppressive condition.
  • Documented HIV, hepatitis B and C positive subject.
  • Any condition which, in the opinion of the investigator, may pose an increased and unreasonable safety risk to the subject if they participated in the study.
  • Subjects with a baseline neutrophil count below 1800 cells per microliter (cells/µL) lower limit of normal range (LLN) OR with clinically significant abnormalities in other laboratory values, according to local reference ranges and investigator judgment.
  • Previous history of Benign Ethnic Neutropenia, or drug related Neutropenia.
  • Concomitant treatment with neutropenic agents.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03527173


Locations
Layout table for location information
United States, Ohio
GSK Investigational Site
Cincinnati, Ohio, United States, 45229
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Layout table for investigator information
Study Director: GSK Clinical Trials GlaxoSmithKline

Layout table for additonal information
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03527173     History of Changes
Other Study ID Numbers: 205626
H03_03TP ( Other Identifier: GSK Vaccines Institute for Global Health )
First Posted: May 17, 2018    Key Record Dates
Last Update Posted: June 14, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:
Challenge
Efficacy
Shigellosis
Vaccination

Additional relevant MeSH terms:
Layout table for MeSH terms
Dysentery
Dysentery, Bacillary
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Vaccines
Immunologic Factors
Physiological Effects of Drugs