Clinical trial NCT03840811: Experimental Human Infection With Neisseria Gonorrhoeae
Official title: Experimental Human Infection With Isogenic Mutants of Neisseria Gonorrhoeae
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Gonococcal Infection
Keywords: ceftriaxone
challenge
ciprofloxacin
males
Neisseria gonorrhoeae
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2019-02-15
Enrollment: 27
Sex: MALE
Minimum age (years): 18
Maximum age (years): 36
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: 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
timeFrame: Baseline and the day of treatment, any day between Day 2 and Day 6
measure: 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
timeFrame: day of infection, any day between Day 2 and Day 6
measure: Proportion of Participants That Become Infected as Defined by a Positive Urine or Urethral Swab Culture for Infections Initiated With Mixed Inocula
timeFrame: day of infection, any day between Day 2 and Day 6
Secondary outcomes:
measure: Median Time From Inoculation to Treatment Among Infected Participants by Day 6, by Strain, in Non-competitive Infections
timeFrame: Day 2 through the day of treatment, up to Day 6
measure: Proportion of Participants With Occurrence of Bacteriuria in Non-competitive Infections, by Strain
timeFrame: Day of occurrence, any day between Day 2 and Day 6
measure: Proportion of Participants With Occurrence of Signs and Symptoms of Urethritis Attributable to Gonococcal Infection in Non-competitive Infections, by Strain
timeFrame: Day of occurrence, any day between Day 2 and Day 6
measure: Proportion of Participants With Occurrence of Urethritis in Non-competitive Infections
timeFrame: Day of occurrence, any day between Day 2 and Day 6
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina Health Care - Infectious Diseases
state: North Carolina
Study officials:
References: