Experimental Human Infection With Neisseria Gonorrhoeae

• ClinicalTrials.gov Identifier: NCT03840811
• Recruitment Status: Completed
• First Posted: February 15, 2019
• Results First Posted: March 23, 2021
• Last Update Posted: March 23, 2021
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Gonococcal Infection	Drug: Cefixime; Drug: Ceftriaxone; Drug: Ciprofloxacin; Biological: Neisseria gonorrhoeae strain FA1090 A26; Biological: Neisseria gonorrhoeae strain FA7537	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Experimental Human Infection With Isogenic Mutants of Neisseria Gonorrhoeae
• Actual Study Start Date: April 23, 2017
• Actual Primary Completion Date: November 25, 2019
• Actual Study Completion Date: November 25, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group 1; Subjects (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain	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 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
Experimental: Group 2; Subjects (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain.	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.
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	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

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: Baseline and the day of treatment, any day between Day 2 and Day 6 ]

   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.

2. 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 [ Time Frame: day of infection, any day between Day 2 and Day 6 ]
   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.
3. Proportion of Participants That Become Infected as Defined by a Positive Urine or Urethral Swab Culture for Infections Initiated With Mixed Inocula [ Time Frame: day of infection, any day between Day 2 and Day 6 ]
   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.

Secondary Outcome Measures :

1. Median Time From Inoculation to Treatment Among Infected Participants by Day 6, by Strain, in Non-competitive Infections [ Time Frame: Day 2 through the day of treatment, up to Day 6 ]
   The median time from inoculation to antibiotic treatment were calculated for each group.
2. Proportion of Participants With Occurrence of Bacteriuria in Non-competitive Infections, by Strain [ Time Frame: Day of occurrence, any day between Day 2 and Day 6 ]
   Bacteriuria is defined as Log10 cfu N. gonorrhoeae/mL urine sediment.
3. Proportion of Participants With Occurrence of Signs and Symptoms of Urethritis Attributable to Gonococcal Infection in Non-competitive Infections, by Strain [ Time Frame: Day of occurrence, any day between Day 2 and Day 6 ]
   Participants with any subjective symptoms or objective signs (observed urethral discharge) during period 01 (post-inoculation and before treatment which can occur on or before day 6) from the Solicited Events Form were captured.
4. Proportion of Participants With Occurrence of Urethritis in Non-competitive Infections [ Time Frame: Day of occurrence, any day between Day 2 and Day 6 ]
   Urethritis is defined as >= 5.8 Log10 WBC/mL urine sediment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 36 Years (Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, North Carolina

University of North Carolina Health Care - Infectious Diseases

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

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Protocol and Statistical Analysis Plan  [PDF] August 9, 2019

More Information

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT03840811
• Other Study ID Numbers: 09-0106
• First Posted: February 15, 2019
• Results First Posted: March 23, 2021
• Last Update Posted: March 23, 2021
• Last Verified: September 16, 2020

• 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

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

ceftriaxone; challenge; ciprofloxacin; males; Neisseria gonorrhoeae

Additional relevant MeSH terms:

Infections; Communicable Diseases; Gonorrhea; Disease Attributes; Pathologic Processes; Neisseriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Sexually Transmitted Diseases, Bacterial; Sexually Transmitted Diseases; Genital Diseases; Urogenital Diseases; Ciprofloxacin; Ceftriaxone; Cefixime; Anti-Bacterial Agents; Anti-Infective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Third Generation Cephalosporins; Beta Lactam Antibiotics