Back to resultsExperimental Human Infection With Neisseria Gonorrhoeae
Primary Purpose
Gonococcal Infection
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cefixime
Ceftriaxone
Ciprofloxacin
Neisseria gonorrhoeae strain FA1090 A26
Neisseria gonorrhoeae strain FA7537
Sponsored by
About this trial
This is an interventional basic science trial for Gonococcal Infection focused on measuring ceftriaxone, challenge, ciprofloxacin, males, Neisseria gonorrhoeae
Eligibility Criteria
Inclusion Criteria:
- 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)
- Denies history of cancer, except basal cell carcinoma of the skin > 5 years ago
- Denies history of drug abuse
- Denies history of genitourinary surgery
Exclusion Criteria:
- 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)
- Hemoglobin level < 12.0 g/dL or above ULN and deemed clinically significant by the study physician
- Urinalysis: Qualitative protein level > 1+ or RBC count > 10/hpf
Medications not permitted with cefixime or ceftriaxone:
- Warfarin
- Probenecid
- Aspirin
- Diuretics such as furosemide
- Aminoglycoside antibiotics
- Chloramphenicol
Medications not permitted with ciprofloxacin:
- Tizanidine
- Theophylline
- Warfarin
- Glyburide
- Cyclosporine
- Probenecid
- Phenytoin
- Methotrexate
- Antacids, multivitamins, and other dietary supplements containing magnesium, calcium, aluminum, iron or zinc
- Caffeine-containing medications
- Sucralfate or didanosine chewable or buffered tablets
Sites / Locations
- University of North Carolina Health Care - Infectious Diseases
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Group 1
Group 2
Group 3
Arm Description
Subjects (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain
Subjects (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain.
Subjects (n= up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT strain
Outcomes
Primary Outcome Measures
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.
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.
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.
Secondary Outcome Measures
Median Time From Inoculation to Treatment Among Infected Participants by Day 6, by Strain, in Non-competitive Infections
The median time from inoculation to antibiotic treatment were calculated for each group.
Proportion of Participants With Occurrence of Bacteriuria in Non-competitive Infections, by Strain
Bacteriuria is defined as Log10 cfu N. gonorrhoeae/mL urine sediment.
Proportion of Participants With Occurrence of Signs and Symptoms of Urethritis Attributable to Gonococcal Infection in Non-competitive Infections, by Strain
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.
Proportion of Participants With Occurrence of Urethritis in Non-competitive Infections
Urethritis is defined as >= 5.8 Log10 WBC/mL urine sediment.
Full Information
NCT ID
NCT03840811
First Posted
February 7, 2019
Last Updated
February 26, 2021
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
1. Study Identification
Unique Protocol Identification Number
NCT03840811
Brief Title
Experimental Human Infection With Neisseria Gonorrhoeae
Official Title
Experimental Human Infection With Isogenic Mutants of Neisseria Gonorrhoeae
Study Type
Interventional
2. Study Status
Record Verification Date
September 16, 2020
Overall Recruitment Status
Completed
Study Start Date
April 23, 2017 (Actual)
Primary Completion Date
November 25, 2019 (Actual)
Study Completion Date
November 25, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
4. Oversight
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
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gonococcal Infection
Keywords
ceftriaxone, challenge, ciprofloxacin, males, Neisseria gonorrhoeae
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
27 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Group 1
Arm Type
Experimental
Arm Description
Subjects (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain
Arm Title
Group 2
Arm Type
Experimental
Arm Description
Subjects (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain.
Arm Title
Group 3
Arm Type
Experimental
Arm Description
Subjects (n= up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT strain
Intervention Type
Drug
Intervention Name(s)
Cefixime
Intervention Description
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
Intervention Name(s)
Ceftriaxone
Intervention Description
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
Intervention Name(s)
Ciprofloxacin
Intervention Description
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
Biological
Intervention Name(s)
Neisseria gonorrhoeae strain FA1090 A26
Intervention Description
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
Intervention Name(s)
Neisseria gonorrhoeae strain FA7537
Intervention Description
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
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Baseline and the day of treatment, any day between Day 2 and Day 6
Title
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
Description
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.
Time Frame
day of infection, any day between Day 2 and Day 6
Title
Proportion of Participants That Become Infected as Defined by a Positive Urine or Urethral Swab Culture for Infections Initiated With Mixed Inocula
Description
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.
Time Frame
day of infection, any day between Day 2 and Day 6
Secondary Outcome Measure Information:
Title
Median Time From Inoculation to Treatment Among Infected Participants by Day 6, by Strain, in Non-competitive Infections
Description
The median time from inoculation to antibiotic treatment were calculated for each group.
Time Frame
Day 2 through the day of treatment, up to Day 6
Title
Proportion of Participants With Occurrence of Bacteriuria in Non-competitive Infections, by Strain
Description
Bacteriuria is defined as Log10 cfu N. gonorrhoeae/mL urine sediment.
Time Frame
Day of occurrence, any day between Day 2 and Day 6
Title
Proportion of Participants With Occurrence of Signs and Symptoms of Urethritis Attributable to Gonococcal Infection in Non-competitive Infections, by Strain
Description
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.
Time Frame
Day of occurrence, any day between Day 2 and Day 6
Title
Proportion of Participants With Occurrence of Urethritis in Non-competitive Infections
Description
Urethritis is defined as >= 5.8 Log10 WBC/mL urine sediment.
Time Frame
Day of occurrence, any day between Day 2 and Day 6
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
36 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
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)
Denies history of cancer, except basal cell carcinoma of the skin > 5 years ago
Denies history of drug abuse
Denies history of genitourinary surgery
Exclusion Criteria:
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)
Hemoglobin level < 12.0 g/dL or above ULN and deemed clinically significant by the study physician
Urinalysis: Qualitative protein level > 1+ or RBC count > 10/hpf
Medications not permitted with cefixime or ceftriaxone:
Warfarin
Probenecid
Aspirin
Diuretics such as furosemide
Aminoglycoside antibiotics
Chloramphenicol
Medications not permitted with ciprofloxacin:
Tizanidine
Theophylline
Warfarin
Glyburide
Cyclosporine
Probenecid
Phenytoin
Methotrexate
Antacids, multivitamins, and other dietary supplements containing magnesium, calcium, aluminum, iron or zinc
Caffeine-containing medications
Sucralfate or didanosine chewable or buffered tablets
Facility Information:
Facility Name
University of North Carolina Health Care - Infectious Diseases
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514-4220
Country
United States
12. IPD Sharing Statement
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Experimental Human Infection With Neisseria Gonorrhoeae
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