Clinical trial NCT04870138: Experimental Human Infection With Neisseria Gonorrhoeae (LptA Trial)
Official title: Experimental Human Infection With Isogenic Mutants of Neisseria Gonorrhoeae (LptA Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Gonococcal Infection
Keywords: ceftriaxone
challenge
ciprofloxacin
males
Neisseria gonorrhoeae
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2021-05-03
Enrollment: 16
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This is a Phase 1, interventional, non-randomized, experimental infection model study in healthy adult males (N=up to 25) between the ages of 18-35 at study enrollment. The study is designed to test the requirements of predicted N. gonorrhoeae virulence determinants for gonococcal infection in the male urethra through infection with engineered mutants of N. gonorrhoeae. We predict that mutations abolishing expression of N. gonorrhoeae virulence determinants will eliminate or significantly reduce gonococcal infectivity or the ability to induce inflammation in an infected individual, thus identifying potential vaccine candidates. Study duration will be 1 year, and the duration for all participants will be about 3 weeks. The primary objective of the study is to compare the ability of different engineered mutants of Neisseria gonorrhoeae to cause a clinical infection (signs or symptoms of urethritis such as discomfort during urination, urethral discharge, etc.) in the male urethra.

Detailed description: This is a Phase 1, interventional, non-randomized, experimental infection model study in healthy adult males (N=up to 25) between the ages of 18-35 at study enrollment. The study is designed to test the requirements of predicted N. gonorrhoeae virulence determinants for gonococcal infection in the male urethra through infection with engineered mutants of N. gonorrhoeae. We hypothesize that key virulence determinants involved in N. gonorrhoeae adherence and resistance to innate immunity are essential for infection in the male urethra. We predict that mutations abolishing expression of these virulence determinants will eliminate or significantly reduce gonococcal infectivity or the ability to induce inflammation in an infected individual, thus identifying potential vaccine candidates. For each mutant to be investigated under this protocol, initial trials will be conducted in which subjects receive a bacterial inoculum containing a mixture of equivalent numbers of two isogenic strains, differing in expression of one or more genes. A competitive advantage for one strain during urethral infection will be manifest by recovery of that strain in a statistically significantly higher proportion of isolates recovered from infected subjects than in the inoculum. Following infections with mixed inocula, infectivity of the mutant in single-strain infections will be compared to that of the wild-type in single-strain infections. In addition, the proportion of infected subjects that develop signs or symptoms of urethritis with mutant and wild- type inocula will be compared. The Mixed FA7527/FA1090 group (n = up to 25 ) will receive a bacterial inoculum containing a mixture of equivalent numbers of the isogenic mutant and WT strains. In single-strain infections, the Mutant FA7527 group (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain, and the Wild-type FA1090 group (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain. All subjects will be examined daily for symptoms of infection and receive antibiotic treatment at the end of the inpatient portion of the trial. Study duration will be 1 year, and the duration for all participants will be about 3 weeks. The primary objective of the study is to compare the ability of different engineered mutants of Neisseria gonorrhoeae to cause a clinical infection (signs or symptoms of urethritis such as discomfort during urination, urethral discharge, etc.) in the male urethra. The study secondary objectives are to: (1) characterize host immune responses to infection by measuring cytokines and other mediators in specimens including serum, peripheral blood lymphocytes and urine obtained from subjects before, during and after experimental gonococcal infection, and (2) characterize bacterial gene expression during experimental infection.

Eligibility criteria: Inclusion Criteria:

1. Healthy man between the ages of 18 and 35 years.
2. Able and willing to be located easily by providing street address and telephone number (land line and/or cell phone number).
3. Willingness to provide written informed consent.
4. Able and willing to attend all study visits including 6-day stay in the Clinical and Translational Research Center (CTRC) during the trial (with ability to leave the unit during the day) and follow-up visit during the week after treatment.
5. Able and willing to abstain from masturbation during the 6-day stay in the CTRC.
6. Able and willing to abstain from all sexual activity during the course of the study.
7. Acceptable medical history by screening evaluation.
8. Standard physical exam within normal limits (WNL).
9. Serum creatinine WNL.
10. Serum alanine transaminase (ALT) WNL.
11. White blood cell (WBC), polymorphonuclear cell (PMN) and hemoglobin values WNL.
12. Normal urinalysis.
13. Total Complement (CH50) WNL.
14. Urine negative for chlamydia, gonorrhea, trichomonas and mycoplasma.
15. Negative HIV, syphilis, and Hepatitis C (HCV) test results.
16. Negative Hepatitis B (HBV) core and surface antibodies or results consistent with immunization (negative HBV core antibody/positive HBV surface antibody).
17. Denies history of STIs including syphilis and hepatitis B \& C.
18. Denies history of bleeding diathesis.
19. Denies history of seizures (due to reports of seizures with ciprofloxacin).
20. Denies history of cancer, except basal cell carcinoma of the skin more than 5 years ago.
21. Denies history of drug abuse.
22. Denies history of psychiatric disorders, except depression controlled by medication.
23. Denies history of genitourinary surgery.

Exclusion Criteria:

1. Student or employee under the direct supervision of any of the study investigators.
2. Any known immunodeficiencies including complement deficiency, antibody deficiency, chronic granulomatous disease or HIV infection.
3. Psychiatric disorders that would interfere with the integrity of the data or volunteer safety.
4. Unstable depression (defined as receiving either \< 3 months of the same medication (and dose) or a decompensating event during the previous 3 months) or depression that, in the opinion of the investigator, will compromise the subject's ability to comply with protocol requirements.
5. Heart murmur or heart disease.
6. Anatomic abnormality of the urinary tract.
7. Any antibiotic treatment in the past 30 days, or azithromycin in the past 60 days.
8. Chemotherapy within the past year.
9. Current steroid use, except for topical application.
10. Allergy to penicillin, ceftriaxone or ciprofloxacin or to lidocaine.
11. Treatment with medications that are contraindicated with ciprofloxacin or ceftriaxone and that cannot be withheld for the single doses given in this study.

Primary outcomes:
measure: The Proportion of Participants That Become Infected With Individual N. Gonorrhoeae Strains in Non-competitive Infections
timeFrame: Day of infection, any day between Day 1 and Day 5
measure: The Proportion of Participants That Become Infected With Mixed Inoculum
timeFrame: Day of infection, any day between Day 1 and Day 5
measure: The Proportion of Wild Type (WT) Organisms Recovered From Urine and Urethral Swab Specimens From Individual Subjects Infected With Mixed Inoculum
timeFrame: Baseline (Day 0) and the day of infection (any day between Day 1 and Day 5)
Secondary outcomes:
measure: EGF Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: Eotaxin Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: G-CSF Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: Fractalkine Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: GRO Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: IL-1RA Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: IL-8 Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: IP-10 Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: MCP-1 Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: MIP-1Beta Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: VEGF Cytokine Levels in Peripheral Blood
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: EGF Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: Eotaxin Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: G-CSF Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: Fractalkine Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: GRO Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: IL-1RA Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: IL-8 Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: IP-10 Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: MCP-1 Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: MIP-1Beta Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: VEGF Cytokine Levels in Urine
timeFrame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
measure: Pattern of Gonococcal Gene Expression in Urine Sediment
timeFrame: Day 1 through Day 5
measure: Quantity of Gonococcal Gene Expression in Urine Sediment
timeFrame: Day 1 through Day 5
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina Health Care - Infectious Diseases
state: North Carolina
Study officials:
References: