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Sm-TSP-2 Schistosomiasis Vaccine in Healthy Ugandan Adults

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ClinicalTrials.gov Identifier: NCT03910972
Recruitment Status : Recruiting
First Posted : April 10, 2019
Last Update Posted : January 26, 2021
Sponsor:
Collaborators:
George Washington University
Makerere University Walter Reed Project
Information provided by (Responsible Party):
Maria Elena Bottazzi PhD, Baylor College of Medicine

Tracking Information
First Submitted Date  ICMJE April 9, 2019
First Posted Date  ICMJE April 10, 2019
Last Update Posted Date January 26, 2021
Actual Study Start Date  ICMJE October 7, 2019
Estimated Primary Completion Date October 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2019)
  • Safety and Tolerability: frequency of local and systemic reactogenicity events [ Time Frame: 7 days post-vaccination ]
    Frequency of solicited injection site and systemic reactogenicity, graded by severity, on the day of each study vaccination through 7 days after each study vaccination.
  • Safety and Tolerability: frequency of unsolicited adverse events [ Time Frame: 28 days post-vaccination ]
    Frequency of unsolicited adverse events, graded by severity, from the time of each study vaccination through approximately 1 month after each study vaccination.
  • Safety and Tolerability: frequency of vaccine-related Serious Adverse Events [ Time Frame: 23 months ]
    Frequency of study vaccine-related Serious Adverse Events from the time of the first study vaccination through the final study visit.
  • Safety and Tolerability: frequency of clinical safety laboratory adverse events [ Time Frame: 7 days post-vaccination ]
    Frequency of clinical safety laboratory adverse events measured 7 days after each vaccination
  • Safety and Tolerability: frequency of new-onset chronic medical conditions [ Time Frame: 23 months ]
    Frequency of new-onset chronic medical conditions, including Adverse Events of Special Interest, through the final study visit
  • Efficacy: proportion of subjects with detectable S. mansoni eggs [ Time Frame: 12 and 23 months ]
    Proportion of subjects with detectable S. mansoni eggs at 12 and 23 months in fecal samples, as determined by Kato Katz fecal thick smear.
  • Efficacy: mean S. mansoni eggs per gram of feces [ Time Frame: 12 and 23 months ]
    Mean S. mansoni eggs per gram as determined by fecal microscopy (Kato Katz fecal thick smear) at 12 and 23 months.
  • Efficacy: Proportion of subjects with a positive CAA test [ Time Frame: 12 and 23 months ]
    Proportion of subjects with a positive CAA test at 12 and 23 months.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2019)
  • Immunogenicity: peak anti-Sm-TSP-2 IgG level [ Time Frame: Day 126 ]
    IgG level by qualified indirect ELISA on approximately Day 126
  • Immunogenicity: anti-Sm-TSP-2 IgG levels over time [ Time Frame: Approximately 14 days after doses one and two and at Days 200, 290, 380 (Parts A and B) after final dose, and at Days 548, and 800 (Part B) after final dose. ]
    IgG antibody response measured by qualified indirect ELISA
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 9, 2019)
  • Efficacy: CAA (Part B only) [ Time Frame: 12 and 23 months following final vaccination ]
    Proportion of subjects with a positive CAA test
  • Efficacy: fecal Schistosomal DNA [ Time Frame: 12 and 23 months following final vaccination ]
    Levels of Schistosoma DNA in fecal samples, as measured by real-time PCR.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Sm-TSP-2 Schistosomiasis Vaccine in Healthy Ugandan Adults
Official Title  ICMJE A Phase I/II Trial of the Safety, Immunogenicity, and Efficacy of the Sm-TSP-2/Alhydrogel® Schistosomiasis Vaccine in Healthy Exposed Ugandan Adults
Brief Summary

The study will recruit up to 290 healthy adult males and non-pregnant females into a two-part clinical trial of a vaccine to protect against schistosomiasis caused by infection with S. mansoni. Two formulations of the Sm-TSP-2 vaccine will be tested: one using Alhydrogel® only, and one using Alhydrogel® plus AP 10-701, each at 3 different doses of antigen: 10mcg, 30mcg, and 100mcg.

The first part of the study will be a Phase I dose-escalation safety and immunogenicity study followed by a Phase IIb trial in which a larger number of adults will be enrolled to assess the impact of the vaccine on infection with S. mansoni. The impact of the vaccine on infection with S. haematobium will also be assessed although this will be exploratory given that potential cross-protection against this species is only hypothetical at this point.

Detailed Description

The study will recruit up to 290 healthy adult males and non-pregnant females into a two-part clinical trial of a vaccine to protect against schistosomiasis caused by infection with S. mansoni. Two formulations of the Sm-TSP-2 vaccine will be tested: one using Alhydrogel® only, and one using Alhydrogel® plus AP 10-701, each at 3 different doses of antigen: 10mcg, 30mcg, and 100mcg.

The first part of the study will be a Phase I dose-escalation safety and immunogenicity study followed by a Phase IIb trial in which a larger number of adults will be enrolled to assess the impact of the vaccine on infection with S. mansoni. The impact of the vaccine on infection with S. haematobium will also be assessed although this will be exploratory given that potential cross-protection against this species is only hypothetical at this point.

Part A: double blind (within cohort), randomized, controlled, dose-escalation Phase 1b clinical trial in S. mansoni exposed adults living in the area of Kampala, Uganda. In each of 3 cohorts, subjects will be randomly assigned to 1 of 3 groups: Sm-TSP-2/Alhydrogel®, Sm-TSP-2/Alhydrogel®/AP 10-701, or the licensed Hepatitis B vaccine (up to 12 subjects per study vaccine group and 6 subjects in the Hepatitis B vaccine group). Subjects will receive three doses of the assigned vaccine delivered intramuscularly at approximately Days 0, 56, and 112.

Safety will be measured from the time of each study vaccination (Days 0, 56, 112 [Visits 2, 7, 12]) through 7 days after each study vaccination by the occurrence of solicited injection site and systemic reactogenicity events. Unsolicited non-serious adverse events (AEs) will be collected from the time of each study vaccination through approximately 28 days after each study vaccination. New-onset chronic medical conditions (including adverse events of special interest [AESI]) and serious adverse events (SAEs) will be collected from the time of the first study vaccination (Day 0 [Visit 2]) through approximately 9 months after the third study vaccination (Day 380 [Visit 19]). Clinical laboratory evaluations for safety will be performed on venous blood collected approximately 7 days after each study vaccination.

Immunogenicity testing will include IgG antibody responses to Sm-TSP-2 by a qualified indirect ELISA on serum obtained prior to each study vaccination (Days 0, 56, 112) and at time points after each vaccination.

Ninety subjects will be enrolled into 3 groups of 30. Recruitment and enrollment into the study will occur on an ongoing basis, with each group being recruited and vaccinated in sequence.

Part A of the study is a dose escalation trial in which escalation to the next dose cohort will be determined based on evaluation of pre-defined escalation criteria, which will be evaluated 7 days after all subjects in the currently active cohort have received their first dose of vaccine. Within each cohort, the assignment to Alhydrogel®, Alhydrogel®/AP 10-701, or Hepatitis B vaccine will be randomized and double-blinded (i.e., neither the subject nor the investigator will be aware of the formulation assigned). The study will proceed as follows:

  1. Cohort 1, N=30 [10mcg Sm-TSP-2/Alhydrogel® (n=12) or 10mcg Sm-TSP-2/Alhydrogel®/ AP 10-701 (n=12) or Hepatitis B vaccine (n=6)]

    1. Enroll, randomize, and administer first dose of study vaccine or Hepatitis B vaccine to initial 6 subjects
    2. After initial 6 subjects have completed Visit 3, administer the first dose of study vaccine or Hepatitis B vaccine to the remaining 24 subjects
    3. Assess 7 day post dose 1 safety data for all subjects
    4. Make escalation decision
  2. Cohort 2, N=30 [30mcg Sm-TSP-2/Alhydrogel® (n=12) or 30mcg Sm-TSP-2/Alhydrogel®/AP 10-701 (n=12) or Hepatitis B vaccine (n=6)]

    1. Enroll, randomize, and administer first dose of study vaccine or Hepatitis B vaccine to initial 6 subjects
    2. After initial 6 subjects have completed Visit 3, administer the first dose of study vaccine or Hepatitis B vaccine to the remaining 24 subjects
    3. Assess 7 day post dose 1 safety data for all subjects
    4. Make escalation decision
  3. Cohort 3, N=30 [100mcg Sm-TSP-2/Alhydrogel® (n=12) or 100mcg Sm-TSP-2/Alhydrogel®/AP 10-701 (n=12) or Hepatitis B vaccine (n=6)]

    1. Enroll, randomize, and administer first dose of study vaccine or Hepatitis B vaccine to initial 6 subjects
    2. After initial 6 subjects have completed Visit 3, administer the first dose of study vaccine or Hepatitis B vaccine to remaining 24 subjects
    3. Assess 7 day post dose 1 safety data for all subjects
    4. Complete follow-up for all subjects
    5. Close the study

Part B: double blind, randomized, controlled, dose-escalation Phase IIb clinical trial in adults living in the area of Kampala, Uganda, who reside in S. mansoni endemic areas with greater than or equal to 25% prevalence in children aged 5-15 years of age. In this part of the study, up to 200 eligible Schistosoma-positive (by Kato Katz fecal thick smear or CAA) adult volunteers will be progressively enrolled and randomized to receive either Sm-TSP-2/Alhydrogel® (with or without AP 10-701) or the Hepatitis B comparator vaccine, in a 1:1 fashion. The dose and formulation (i.e., with or without the point-of-injection addition of AP 10-701) of Sm-TSP-2/Alhydrogel® that will be tested in this part of the study will be chosen based on the interim results of Part A of the trial after all participants have received their third dose of vaccine. All participants in Part B will be treated with praziquantel prior to receipt of the first vaccination.

Interim safety and anti-Sm-TSP-2 IgG antibody results up to and including Day 126 of Part A of the trial will be evaluated to determine the dose that will be tested in Part B.

Two hundred subjects will be enrolled in Part B. The 12 subjects in Part A who received the same dose/formulation of Sm-TSP-2/Alhydrogel® that is chosen for Part B will be offered the opportunity to transition to Part B for the remainder of their participation in the study.

Recruitment and enrollment into the study will occur on an ongoing basis, with participants being recruited, randomized and vaccinated in sequence. Within Part B, the assignment to Sm-TSP-2/Alhydrogel® or Hepatitis B vaccine will be randomized and double-blinded (i.e., neither the subject nor the investigator will be aware of the formulation assigned). Part B of the study will proceed as follows:

1. Cohort 4, N=200 [Sm-TSP-2/Alhydrogel® [dose and formulation TBD] (n=100) or Hepatitis B vaccine (n=100)]

Subjects will receive three doses of the assigned vaccine delivered intramuscularly at approximately Days 0, 56, and 112.

Safety will be measured from the time of each study vaccination (Days 0, 56, 112 [Visits 2, 7, 12]) through 7 days after each study vaccination by the occurrence of solicited injection site and systemic reactogenicity events. Unsolicited non-serious adverse events (AEs) will be collected from the time of each study vaccination through approximately 28 days after each study vaccination. New-onset chronic medical conditions (including adverse events of special interest [AESI]) and serious adverse events (SAEs) will be collected from the time of the first study vaccination (Day 0 [Visit 2]) through approximately 23 months after the third study vaccination (Day 800 [Visit 21]). Clinical laboratory evaluations for safety will be performed on venous blood collected approximately 7 days after each study vaccination.

Immunogenicity testing will include IgG antibody responses to Sm-TSP-2 by a qualified indirect ELISA on serum obtained prior to each study vaccination (Days 0, 56, 112) and at time points after each vaccination.

Efficacy will be evaluated by measuring the impact of vaccination with Sm-TSP-2/Alhydrogel® on fecal and urine Schistosoma egg counts and CAA positivity. After final vaccination, fecal and urine samples will be collected at 12 and 23 months following the final vaccination to determine rates and intensities of re-infection. The primary endpoint to determine the impact of vaccination on infection with S. mansoni will be incidence of infection as determined by a positive CAA test or Kato-Katz fecal thick smear. The impact of vaccination on infection with S. haematobium will be assessed as an exploratory endpoint, by means of urine microscopy for schistosome eggs.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Schistosomiasis
  • Schistosoma Mansoni
Intervention  ICMJE
  • Biological: Sm-TSP-2/Alhydrogel® vaccine
    The Sm-TSP-2/Alhydrogel® candidate vaccine contains recombinant Sm-TSP-2 adsorbed onto aluminum hydroxide gel (Alhydrogel®) and suspended in a solution containing 10mM imidazole buffer containing 2mM phosphate and 15% sucrose, with pH 7.4 ± 0.1. The final concentrations of Sm-TSP-2 and Alhydrogel® in the drug product are 0.1mg/ml and 0.8mg/ml respectively.
  • Biological: Sm-TSP-2/Alhydrogel® vaccine plus AP 10-701
    The Sm-TSP-2/Alhydrogel® candidate vaccine co-administered with the immunostimulant, AP 10-701. b) AP 10-701, also known as Gluco-Pyranosylphospho-Lipid A Aqueous Formulation (GLA-AF), is a Toll-like Receptor-4 agonist. Point-of-injection formulations with this immunostimulant will be prepared immediately prior to vaccination by adding an appropriate volume of AP 10-701 to Sm-TSP-2/Alhydrogel® and withdrawing an appropriate volume to administer the desired amount of Sm-TSP-2 plus 5µg GLA-AF.
  • Biological: ENGERIX-B Hepatitis B Vaccine
    Recombinant hepatitis B vaccine containing 10 mcg recombinant hepatitis B surface antigen per dose
Study Arms  ICMJE
  • Experimental: Part A, Group A (Sm-TSP-2/Alhydrogel 10 mcg)
    Sm-TSP-2/Alhydrogel Schistosomiasis Vaccine, delivered by IM injection on study days 0, 56, and 12; 10 mcg dose
    Intervention: Biological: Sm-TSP-2/Alhydrogel® vaccine
  • Experimental: Part A, Group B (Sm-TSP-2/Alhydrogel 10 mcg + AP 10-701)
    Sm-TSP-2/Alhydrogel Schistosomiasis Vaccine plus AP 10-701, delivered by IM injection on study days 0, 56, and 12; 10 mcg dose
    Intervention: Biological: Sm-TSP-2/Alhydrogel® vaccine plus AP 10-701
  • Experimental: Part A, Group C (Sm-TSP-2/Alhydrogel 30 mcg)
    Sm-TSP-2/Alhydrogel Schistosomiasis Vaccine, delivered by IM injection on study days 0, 56, and 12; 30 mcg dose
    Intervention: Biological: Sm-TSP-2/Alhydrogel® vaccine
  • Experimental: Part A, Group D (Sm-TSP-2/Alhydrogel 30 mcg + AP 10-701)
    Sm-TSP-2/Alhydrogel Schistosomiasis Vaccine plus AP 10-701, delivered by IM injection on study days 0, 56, and 12; 30 mcg dose
    Intervention: Biological: Sm-TSP-2/Alhydrogel® vaccine plus AP 10-701
  • Experimental: Part A, Group E (Sm-TSP-2/Alhydrogel 100 mcg)
    Sm-TSP-2/Alhydrogel Schistosomiasis Vaccine, delivered by IM injection on study days 0, 56, and 12; 100 mcg dose
    Intervention: Biological: Sm-TSP-2/Alhydrogel® vaccine
  • Experimental: Part A, Group F (Sm-TSP-2/Alhydrogel 100 mcg + AP 10-701)
    Sm-TSP-2/Alhydrogel Schistosomiasis Vaccine plus AP 10-701, delivered by IM injection on study days 0, 56, and 12; 100 mcg dose
    Intervention: Biological: Sm-TSP-2/Alhydrogel® vaccine plus AP 10-701
  • Active Comparator: Part A, Group G (HBV)
    Hepatitis B Vaccine
    Intervention: Biological: ENGERIX-B Hepatitis B Vaccine
  • Experimental: Part B, Group H (Sm-TSP-2/Alhydrogel +/- AP 10-701)
    Sm-TSP-2/Alhydrogel Schistosomiasis Vaccine, with or without AP 10-701, dose and formulation determined in Part A
    Intervention: Biological: Sm-TSP-2/Alhydrogel® vaccine
  • Active Comparator: Part B, Group I (HBV)
    Hepatitis B Vaccine
    Intervention: Biological: ENGERIX-B Hepatitis B Vaccine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 9, 2019)
290
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2023
Estimated Primary Completion Date October 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Provide written informed consent prior to any study procedures.
  2. Able to understand and comply with planned study procedures and be available for all study visits.
  3. Male or non-pregnant female aged 18 to 45, inclusive at the time of enrollment.
  4. Are in good health, as determined by vital signs (oral temperature, pulse, and blood pressure), medical history, and brief physical examination at screening.
  5. Vital signs (oral temperature, pulse, and blood pressure) are all within normal protocol-defined ranges.
  6. Laboratory tests (alanine aminotransferase [ALT], creatinine, white blood cell count (WBC), hemoglobin, and platelets) are all within protocol-defined reference ranges.
  7. Urinalysis with no greater than trace protein and negative for glucose.
  8. Female subjects of childbearing potential must agree to practice highly effective contraception for a minimum of 30 days prior to first vaccination and for 30 days after last vaccination.
  9. Female subjects of childbearing potential must have a negative urine pregnancy test within 24 hours prior to study vaccination.
  10. Able to correctly answer all questions on the informed consent comprehension questionnaire.

Exclusion Criteria:

  1. Has the intention to become pregnant within 5 months after enrollment in this study.
  2. Female subjects who are breastfeeding or plan to breastfeed at any given time from the first study vaccination until 30 days after their last study vaccination.
  3. Has an acute illness, including a documented oral temperature of 38.0°C or greater, within 72 hours prior to vaccination.
  4. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, diabetes, or renal disease by history, physical examination, and/or laboratory studies.
  5. Is immunosuppressed as a result of an underlying illness or treatment.
  6. Using or intends to continue using oral or parenteral steroids, high-dose inhaled steroids (>800 μg/day of beclomethasone dipropionate or equivalent) or other immunosuppressive or cytotoxic drugs.
  7. Positive test for HIV infection.
  8. Volunteer has had a history of alcohol or illicit drug abuse during the past 23 months.
  9. Received immunoglobulin or other blood products (with exception of Rho D immunoglobulin) within 90 days prior to study vaccination.
  10. History of a severe allergic reaction or anaphylaxis to known components of the study vaccines.
  11. Has an acute or chronic medical condition that, in the opinion of the investigator, would render participation in this study unsafe or would interfere with the evaluation of responses.
  12. History of splenectomy.
  13. Is participating or plans to participate in another clinical trial with an interventional agent during the duration of the study.
  14. Received any licensed live vaccine within 30 days or any licensed inactivated vaccine within 14 days prior to the first study vaccination.
  15. Planned receipt of any vaccine from the first study vaccination through 28 days after the last study vaccination.
  16. Has any diagnosis, current or past, of schizophrenia, bipolar disease, or other psychiatric diagnosis that may interfere with subject compliance or safety evaluations.
  17. Has any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol.
  18. Anti-Sm-TSP-2 IgE antibody level above ELISA reactivity threshold.

    Part A Only:

  19. Positive hepatitis B surface antigen (HBsAg).
  20. Positive confirmatory test for hepatitis C virus (HCV) infection.

    Part B Only:

  21. Negative for Schistosoma mansoni eggs, as assessed by the Kato Katz fecal thick smear during screening.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: David J Diemert, MD 2022702393 ddiemert@gwu.edu
Contact: Samantha Daaka, MPH 2029947164 samdaaka@gwu.edu
Listed Location Countries  ICMJE Uganda
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03910972
Other Study ID Numbers  ICMJE H-45791
TSP-18-03 ( Other Identifier: Baylor College of Medicine (Sponsor) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data related to primary and secondary objectives will be made available within 12 months of finalization of the Clinical Study Report.
Time Frame: Within 12 months of finalization of the Clinical Study Report.
Responsible Party Maria Elena Bottazzi PhD, Baylor College of Medicine
Study Sponsor  ICMJE Baylor College of Medicine
Collaborators  ICMJE
  • George Washington University
  • Makerere University Walter Reed Project
Investigators  ICMJE
Principal Investigator: Hannah Kibuuka, MD Makerere University Walter Reed Project
PRS Account Baylor College of Medicine
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP