Experimental Human Infection With Neisseria Gonorrhoeae (LptA Trial)
Condition: Gonococcal Infection
MeSH terms: Infections; Communicable Diseases; Gonorrhea
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Azithromycin; Ceftriaxone; Ciprofloxacin; Neisseria gonorrhoeae strain FA1090 A26; Neisseria gonorrhoeae strain FA7527
Intervention type(s): Drug; Drug; Drug; Biological; Biological
Intervention description(s): Alternative antibiotic treatment failure therapy: Azithromycin 2 g orally in a single dose after treatment failure with both cephalosporin and quinolone antibiotics.; Mandatory antibiotic treatment failure therapy: Ceftriaxone 250 mg intramuscular in a single dose on patient request, at the onset of symptoms, or on the 5th study day after inoculation.; Mandatory antibiotic treatment failure therapy: Ciprofloxacin 500 mg orally in a single dose on patient request, at the onset of symptoms or on the 5th study day after inoculation.; 0.4 mL of a suspension containing 10^5 - 10^6 CFU of wild-type (WT) Neisseria gonorrhoeae, in phosphate-buffered saline, delivered to the anterior urethra through a No.8 pediatric French catheter.; 0.4 mL of a suspension containing 10^5 - 10^6 CFU of isogenic LptA mutant Neisseria gonorrhoeae, in phosphate-buffered saline, delivered to the anterior urethra through a No.8 pediatric French catheter.
Intervention MeSH terms: Azithromycin; Ciprofloxacin; Ceftriaxone
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: ceftriaxone; challenge; ciprofloxacin; males; Neisseria gonorrhoeae