Experimental Human Infection With Neisseria Gonorrhoeae

NCT03840811 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 09-0106
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

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.

Conditions

Gonococcal Infection

Keywords

ceftriaxone; challenge; ciprofloxacin; males; Neisseria gonorrhoeae

Outcome Measures

Primary Outcomes (3)

• The Competitive Index of the Mutant Compared to Wild Type Proportion of Organisms With the Predicted Competitive Advantage Recovered From Urine and/or Urethral Swab Specimens From Infected Participants

  The competitive index (CI) is defined by the ratio of colony forming units (cfu) of the two strains recovered from urine cultures on the day of treatment (output) compared to the ratio of strains in the inoculum (input): CI = mutant cfu(output)/wild-type cfu(output) ÷ mutant cfu(input)/wild-type cfu(input). The CI is used to assess whether the fitness of a given mutant is different than that of wild-type, and CI as a ratio is compared to 1. If it's not significantly different than 1, then no significant difference in the fitness was observed. Mutant or wild-type cfu values of 0 were replaced by 1 in the calculation of competitive index. The assessment was performed in the MtrD trial mixed group.

  Baseline and the day of treatment, any day between Day 2 and Day 6

• Proportion of Participants That Become Infected as Defined by a Positive Urine or Urethral Swab Culture Among Infections Initiated With Individual N. Gonorrhoeae Strains in Non-competitive Infections

  Infection is defined by a positive urine or urethral swab culture. The proportion of infected participants by Day 6 with N. gonorrhoeae was assessed in each trial by group among participants with non-competitive infections. Participants could become infected and received treatment any day before or on day 6.

  day of infection, any day between Day 2 and Day 6

• Proportion of Participants That Become Infected as Defined by a Positive Urine or Urethral Swab Culture for Infections Initiated With Mixed Inocula

  Infection is defined by a positive urine or urethral swab culture. The proportion of infected participants by Day 6 with N. gonorrhoeae was assessed in each trial among participants with infections initiated with mixed inocula. Participants could become infected and received treatment any day before or on day 6.

  day of infection, any day between Day 2 and Day 6

Secondary Outcomes (4)

• Median Time From Inoculation to Treatment Among Infected Participants by Day 6, by Strain, in Non-competitive Infections

  Day 2 through the day of treatment, up to Day 6

• Proportion of Participants With Occurrence of Bacteriuria in Non-competitive Infections, by Strain

  Day of occurrence, any day between Day 2 and Day 6

• Proportion of Participants With Occurrence of Signs and Symptoms of Urethritis Attributable to Gonococcal Infection in Non-competitive Infections, by Strain

  Day of occurrence, any day between Day 2 and Day 6

• Proportion of Participants With Occurrence of Urethritis in Non-competitive Infections

  Day of occurrence, any day between Day 2 and Day 6

Study Arms (3)

Group 1

EXPERIMENTAL

Subjects (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain

Drug: Cefixime; Drug: Ceftriaxone; Drug: Ciprofloxacin; Biological: Neisseria gonorrhoeae strain FA7537

Group 2

EXPERIMENTAL

Subjects (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain.

Drug: Cefixime; Drug: Ceftriaxone; Drug: Ciprofloxacin; Biological: Neisseria gonorrhoeae strain FA1090 A26

Group 3

EXPERIMENTAL

Subjects (n= up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT strain

Drug: Cefixime; Drug: Ceftriaxone; Drug: Ciprofloxacin; Biological: Neisseria gonorrhoeae strain FA1090 A26; Biological: Neisseria gonorrhoeae strain FA7537

Interventions

Cefixime DRUG

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.

Group 1; Group 2; Group 3

Ceftriaxone DRUG

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.

Group 1; Group 2; Group 3

Ciprofloxacin DRUG

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

Group 1; Group 2; Group 3

Neisseria gonorrhoeae strain FA1090 A26 BIOLOGICAL

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.

Group 2; Group 3

Neisseria gonorrhoeae strain FA7537 BIOLOGICAL

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

Group 1; Group 3

Eligibility Criteria

• Age: 18 Years - 36 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy man \> / = 18 and \< 36 years old
• Able and willing to be located easily by providing street address and telephone number (land line and/or cell phone number)
• Willingness to provide written informed consent
• 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
• Able and willing to abstain from all sexual activity until completion of the study and the follow-up test for gonorrhea is negative
• Acceptable medical history by screening evaluation
• No clinically significant abnormalities on physical exam
• Urinalysis: leukocyte esterase, and White Blood Cell (WBC) values within normal limits (WNL)
• CH50 WNL
• Urine negative for chlamydia, gonorrhea, and trichomonas
• Negative Human Immunodeficiency Virus (HIV), syphilis, and Hepatitis C (HCV) test results
• Negative Hepatitis B (HBV) core and surface antibodies or results consistent with immunization (negative HBV core antibody/positive HBV surface antibody)
• Denies history of Sexually Transmitted Infections (STIs) including gonorrhea, chlamydia, syphilis, HIV, HBV, and HCV
• Denies history of bleeding diathesis
• Denies history of seizures (due to reports of seizures with ciprofloxacin)

You may not qualify if:

• Student or employee under the direct supervision of any of the study investigators
• Any known immunodeficiencies including complement deficiency, antibody deficiency, chronic granulomatous disease or Human Immunodeficiency Virus (HIV) infection
• Psychiatric disorders that, in the opinion of the physician, would interfere with the integrity of the data or volunteer safety
• 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
• Heart murmur or heart disease
• Anatomic abnormality of the urinary tract
• Any antibiotic treatment in the past 30 days, or azithromycin in the past 60 days
• Self-reported chemotherapy within the past year
• Current steroid use, except for topical application
• Allergy to penicillin, cephalosporins or ciprofloxacin or to lidocaine
• 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
• Serum creatinine level \< 0.7 or \> 1.75 mg/dL and deemed clinically significant by the study physician
• Serum ALT level \< LLN or \> 105 U/L and deemed clinically significant by the study physician
• WBC count \< 2.5 or \> 15.0 x 10\^9/L and deemed clinically significant by the study physician
• 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)

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

University of North Carolina Health Care - Infectious Diseases

Chapel Hill, North Carolina, 27514-4220, United States

Location

Related Publications (2)

• Waltmann A, Balthazar JT, Begum AA, Hua N, Jerse AE, Shafer WM, Hobbs MM, Duncan JA. Experimental genital tract infection demonstrates Neisseria gonorrhoeae MtrCDE efflux pump is not required for in vivo human infection and identifies gonococcal colonization bottleneck. PLoS Pathog. 2024 Sep 25;20(9):e1012578. doi: 10.1371/journal.ppat.1012578. eCollection 2024 Sep.

  PMID: 39321205 DERIVED

• Waltmann A, Balthazar JT, Begum AA, Hua N, Jerse AE, Shafer WM; UNC-Global Clinical Trials Unit/DMID 09-0106 Study Team; Hobbs MM, Duncan JA. Neisseria gonorrhoeae MtrCDE Efflux Pump During In Vivo Experimental Genital Tract Infection in Men and Mice Reveals the Presence of Within-Host Colonization Bottleneck. medRxiv [Preprint]. 2023 Jun 29:2023.06.23.23291824. doi: 10.1101/2023.06.23.23291824.

  PMID: 37425726 DERIVED

MeSH Terms

Conditions

Gonorrhea

Interventions

Cefixime; Ceftriaxone; Ciprofloxacin

Condition Hierarchy (Ancestors)

Neisseriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Sexually Transmitted Diseases, Bacterial; Sexually Transmitted Diseases; Communicable Diseases; Genital Diseases; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Cefotaxime; Cephacetrile; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines

Results Point of Contact

• Title: Marcia M. Hobbs, PhD
• Organization: University of North Carolina at Chapel Hill

mmhobbs@med.unc.edu

(919) 843-6893

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 7, 2019
• First Posted: February 15, 2019
• Study Start: April 23, 2017
• Primary Completion: November 25, 2019
• Study Completion: November 25, 2019
• Last Updated: March 23, 2021
• Results First Posted: March 23, 2021

Record last verified: 2020-09-16

Locations

US (1)