Experimental Human Infection With Neisseria Gonorrhoeae

NCT ID: NCT03840811

Last Updated: 2021-03-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-23
• Study Completion Date: 2019-11-25

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.

Conditions

Gonococcal Infection

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Group 1

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

Group Type: EXPERIMENTAL

Cefixime

Intervention Type: 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.

Ceftriaxone

Intervention Type: 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.

Ciprofloxacin

Intervention Type: 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

Neisseria gonorrhoeae strain FA7537

Intervention Type: 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

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

Group Type: EXPERIMENTAL

Cefixime

Intervention Type: 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.

Ceftriaxone

Intervention Type: 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.

Ciprofloxacin

Intervention Type: 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

Neisseria gonorrhoeae strain FA1090 A26

Intervention Type: 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 3

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

Group Type: EXPERIMENTAL

Cefixime

Intervention Type: 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.

Ceftriaxone

Intervention Type: 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.

Ciprofloxacin

Intervention Type: 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

Neisseria gonorrhoeae strain FA1090 A26

Intervention Type: 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.

Neisseria gonorrhoeae strain FA7537

Intervention Type: 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

Interventions

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.

Intervention Type: 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.

Intervention Type: 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

Intervention Type: DRUG

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.

Intervention Type: 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

Intervention Type: BIOLOGICAL

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 36 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of North Carolina Health Care - Infectious Diseases

Chapel Hill, North Carolina, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 39321205 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37425726 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

09-0106

Identifier Type: -

Identifier Source: org_study_id