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Experimental Human Infection With Neisseria Gonorrhoeae

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ClinicalTrials.gov Identifier: NCT03840811
Recruitment Status : Recruiting
First Posted : February 15, 2019
Last Update Posted : August 19, 2019
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE February 7, 2019
First Posted Date  ICMJE February 15, 2019
Last Update Posted Date August 19, 2019
Actual Study Start Date  ICMJE April 23, 2017
Estimated Primary Completion Date April 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 12, 2019)
  • The competitive index (CI) of the mutant compared to WT proportion of organisms with the predicted competitive advantage recovered from urine and/or urethral swab specimens from among individual infected subjects [ Time Frame: Day 2 through Day 6 ]
  • The proportion of subjects that become infected as defined by a positive urine or urethral swab culture among infections initiated with individual N. gonorrhoeae strains [ Time Frame: Day 6 ]
  • The proportion of subjects that become infected as defined by a positive urine or urethral swab culture for infections initiated with mixed inocula [ Time Frame: Day 6 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03840811 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 21, 2019)
  • Median time from isogenic mutant N. gonorrhoeae strain inoculation to treatment among infected subjects [ Time Frame: Day 6 ]
  • Median time from wild-type (WT) N. gonorrhoeae strain inoculation to treatment among infected subjects [ Time Frame: Day 6 ]
  • The occurrence of bacteriuria (Log10 cfu N. gonorrhoeae/mL urine sediment) [ Time Frame: Day 2 through Day 6 ]
  • The occurrence of signs and symptoms of urethritis attributable to gonococcal infection [ Time Frame: Day 6 ]
  • The occurrence of urethritis (> 5.8 Log10 WBC/mL urine sediment) [ Time Frame: Day 2 through Day 6 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: February 12, 2019)
  • Median time from isogenic mutant N. gonorrhoeae strain inoculation to treatment among infected subjects [ Time Frame: Day 6 ]
  • Median time from wild-type (WT) N. gonorrhoeae strain inoculation to treatment among infected subjects [ Time Frame: Day 6 ]
  • The occurrence of bacteriuria (Log10 cfu N. gonorrhoeae/mL urine sediment) [ Time Frame: Day 2 through Day 6 ]
  • The occurrence of pyuria (Log10 WBC/mL urine sediment) [ Time Frame: Day 2 through Day 6 ]
  • The occurrence of signs and symptoms of urethritis [ Time Frame: Day 6 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Experimental Human Infection With Neisseria Gonorrhoeae
Official Title  ICMJE Experimental Human Infection With Isogenic Mutants of Neisseria Gonorrhoeae
Brief Summary This is a Phase 1, interventional, non-randomized, experimental infection model study with healthy adult males adults (N=32) between the ages of 18-36 at study enrollment. The study is designed to test the requirements of predicted N. gonorrhoeae virulence determinants for gonococcal infection in the male urethra. The duration for all participants will be about 3 weeks. Study duration will be approximately about 18 months for implementation and enrollment. The primary objectives of the present study are to: (1) compare infectivity of different isogenic mutants with wild-type (WT) N. gonorrhoeae in noncompetitive infections and to (2) assess relative fitness of the mutant in competitive infections initiated by inocula containing equivalent numbers of both WT and mutant strains for mutants with WT infectivity.
Detailed Description This is a Phase 1, interventional, non-randomized, experimental infection model study with healthy adult males adults (N=32) between the ages of 18-36 at study enrollment. The study is designed to test the requirements of predicted N. gonorrhoeae virulence determinants for gonococcal infection in the male urethra. For each mutant to be investigated under this protocol, groups of subjects will be enrolled first in noncompetitive infection studies: Group 1 (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain, and Group 2 (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain. If primary and secondary outcomes are not different for the isogenic mutant and WT strains, a group of subjects will be enrolled in competitive infection studies: Group 3 (up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT 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. Within 7 days of antibiotic treatment, subjects will return for a follow-up examination. A final follow-up phone interview will be conducted within 2 weeks of antibiotic treatment. The duration for all participants will be about 3 weeks. Study duration will be approximately about 18 months for implementation and enrollment. The primary objectives of the present study are to: (1) compare infectivity of different isogenic mutants with wild-type (WT) N. gonorrhoeae in noncompetitive infections and to (2) assess relative fitness of the mutant in competitive infections initiated by inocula containing equivalent numbers of both WT and mutant strains for mutants with WT infectivity. Note, competitive infections will not be performed if non-competitive infections are substantially different. If this is the case, there will be no analysis for this primary objective. The study secondary objective is to compare the clinical course of infection with mutant and WT N. gonorrhoeae in noncompetitive infections.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Gonococcal Infection
Intervention  ICMJE
  • Drug: Cefixime
    Mandatory rescue therapy consisting of cefixime 400 mg orally in a single dose: on patient request, at the onset of symptoms or on the 5th study day after inoculation.
  • Drug: Ceftriaxone
    Mandatory rescue therapy consisting of ceftriaxone 250 mg intramuscularly in a single dose: on patient request, at the onset of symptoms or on the 5th study day after inoculation.
  • Drug: Ciprofloxacin
    Mandatory antibiotic treatment failure therapy: Ciprofloxacin 500 mg orally in a single dose: if the subject has a positie test of cure 1 week post initial antibiotic treatment
  • Biological: Neisseria gonorrhoeae strain FA1090 A26
    0.4 mL of a suspension containing 10^5 - 10^6 CFU of Neisseria gonorrhoeae, in phosphate-buffered saline, delivered to the anterior urethra through a No.8 pediatric French catheter.
  • Biological: Neisseria gonorrhoeae strain FA7537
    0.4 mL of a suspension containing 10^5 - 10^6 CFU of Neisseria gonorrhoeae, in phosphate-buffered saline, delivered to the anterior urethra through a No.8 pediatric French catheter
Study Arms  ICMJE
  • Experimental: Group 1
    Subjects (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain
    Interventions:
    • Drug: Cefixime
    • Drug: Ceftriaxone
    • Drug: Ciprofloxacin
    • Biological: Neisseria gonorrhoeae strain FA7537
  • Experimental: Group 2
    Subjects (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain.
    Interventions:
    • Drug: Cefixime
    • Drug: Ceftriaxone
    • Drug: Ciprofloxacin
    • Biological: Neisseria gonorrhoeae strain FA1090 A26
  • Experimental: Group 3
    Subjects (n= up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT strain
    Interventions:
    • Drug: Cefixime
    • Drug: Ceftriaxone
    • Drug: Ciprofloxacin
    • Biological: Neisseria gonorrhoeae strain FA1090 A26
    • Biological: Neisseria gonorrhoeae strain FA7537
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: February 12, 2019)
32
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 1, 2020
Estimated Primary Completion Date April 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Healthy man > / = 18 and < 36 years old
  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 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 all sexual activity until completion of the study and the follow-up test for gonorrhea is negative
  6. Acceptable medical history by screening evaluation
  7. No clinically significant abnormalities on physical exam
  8. Urinalysis: leukocyte esterase, and White Blood Cell (WBC) values within normal limits (WNL)
  9. CH50 WNL
  10. Urine negative for chlamydia, gonorrhea, and trichomonas
  11. Negative Human Immunodeficiency Virus (HIV), syphilis, and Hepatitis C (HCV) test results
  12. Negative Hepatitis B (HBV) core and surface antibodies or results consistent with immunization (negative HBV core antibody/positive HBV surface antibody)
  13. Denies history of Sexually Transmitted Infections (STIs) including gonorrhea, chlamydia, syphilis, HIV, HBV, and HCV
  14. Denies history of bleeding diathesis
  15. Denies history of seizures (due to reports of seizures with ciprofloxacin)
  16. Denies history of cancer, except basal cell carcinoma of the skin > 5 years ago
  17. Denies history of drug abuse
  18. 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 Human Immunodeficiency Virus (HIV) infection
  3. Psychiatric disorders that, in the opinion of the physician, 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. Self-reported chemotherapy within the past year
  9. Current steroid use, except for topical application
  10. Allergy to penicillin, cephalosporins or ciprofloxacin or to lidocaine
  11. Treatment with medications in the previous month that are contraindicated with cefixime, ceftriaxone or ciprofloxacin and that cannot be withheld for the single doses given in this study
  12. Serum creatinine level < 0.7 or > 1.75 mg/dL and deemed clinically significant by the study physician
  13. Serum ALT level < LLN or > 105 U/L and deemed clinically significant by the study physician
  14. WBC count < 2.5 or > 15.0 x 10^9/L and deemed clinically significant by the study physician
  15. Absolute neutrophil count (ANC) < 1.5 or > 7.5 x 10^9/L and deemed clinically significant by the study physician Exception: For African Americans, ANC values as low as 1.3 x 10^9/L will be allowed (25)
  16. Hemoglobin level < 12.0 g/dL or above ULN and deemed clinically significant by the study physician
  17. Urinalysis: Qualitative protein level > 1+ or RBC count > 10/hpf

Medications not permitted with cefixime or ceftriaxone:

  1. Warfarin
  2. Probenecid
  3. Aspirin
  4. Diuretics such as furosemide
  5. Aminoglycoside antibiotics
  6. Chloramphenicol

Medications not permitted with ciprofloxacin:

  1. Tizanidine
  2. Theophylline
  3. Warfarin
  4. Glyburide
  5. Cyclosporine
  6. Probenecid
  7. Phenytoin
  8. Methotrexate
  9. Antacids, multivitamins, and other dietary supplements containing magnesium, calcium, aluminum, iron or zinc
  10. Caffeine-containing medications
  11. Sucralfate or didanosine chewable or buffered tablets
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 36 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Marcia M Hobbs 19198436893 mmhobbs@med.unc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03840811
Other Study ID Numbers  ICMJE 09-0106
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date March 19, 2019

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