Gonococcal Infection
Conditions
Keywords
ceftriaxone, challenge, ciprofloxacin, males, Neisseria gonorrhoeae
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.
Interventions
DRUGCiprofloxacin
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
DRUGCefixime
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.
DRUGCeftriaxone
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.
BIOLOGICALNeisseria 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.
BIOLOGICALNeisseria 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
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 36 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
| 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 | 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. |
| Proportion of Participants That Become Infected as Defined by a Positive Urine or Urethral Swab Culture for Infections Initiated With Mixed Inocula | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | The median time from inoculation to antibiotic treatment were calculated for each group. |
| Proportion of Participants With Occurrence of Urethritis in Non-competitive Infections | Day of occurrence, any day between Day 2 and Day 6 | Urethritis is defined as \>= 5.8 Log10 WBC/mL urine sediment. |
| Proportion of Participants With Occurrence of Bacteriuria in Non-competitive Infections, by Strain | Day of occurrence, any day between Day 2 and Day 6 | 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 | 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. |
Countries
United States
Participant flow
Recruitment details
Males aged 18-\<36 years old, living in central North Carolina, in general good health with no history of sexually transmitted infection (STIs) were enrolled. Participants were enrolled between 23APR2017 and 10NOV2019.
Participants by arm
| Arm | Count |
|---|---|
| Mutant FA7537 Participants received a bacterial inoculum containing only the isogenic MtrD mutant N. gonorrhoeae strain. | 9 |
| Wild-type FA1090 Participants received a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain. | 6 |
| Mixed FA1090/FA7537 Participants received a bacterial inoculum containing a mixture of equivalent numbers the isogenic MtrD mutant and WT strain. | 12 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Mutant FA7537 | Total | Mixed FA1090/FA7537 | Wild-type FA1090 |
|---|---|---|---|---|
| Age, Continuous | 25.2 years STANDARD_DEVIATION 6.1 | 24.4 years STANDARD_DEVIATION 4.9 | 25.2 years STANDARD_DEVIATION 4.7 | 21.8 years STANDARD_DEVIATION 2.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 24 Participants | 12 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 5 Participants | 5 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 16 Participants | 5 Participants | 5 Participants |
| Region of Enrollment United States | 9 participants | 27 participants | 12 participants | 6 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 27 Participants | 12 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 6 | 0 / 12 |
| other Total, other adverse events | 9 / 9 | 6 / 6 | 12 / 12 |
| serious Total, serious adverse events | 0 / 9 | 0 / 6 | 0 / 12 |
Outcome results
Primary
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.
Time frame: day of infection, any day between Day 2 and Day 6
Population: The evaluable population included participants who received a dose of N. gonorrhoeae within 1 log10 of the intended dose and reached an objective study endpoint (urethral discharge or day 6).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mixed FA1090/FA7537 | 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 | 0.86 proportion of participants |
| Wild-type FA1090 | 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 | 1.00 proportion of participants |
p-value: 0.5495% CI: [-0.58, 0.34]Fisher Exact
Primary
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.
Time frame: day of infection, any day between Day 2 and Day 6
Population: The evaluable population included participants who received a dose of N. gonorrhoeae within 1 log10 of the intended dose and reached an objective study endpoint (urethral discharge or day 6).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mixed FA1090/FA7537 | Proportion of Participants That Become Infected as Defined by a Positive Urine or Urethral Swab Culture for Infections Initiated With Mixed Inocula | 1.00 proportion of participants |
Primary
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.
Time frame: Baseline and the day of treatment, any day between Day 2 and Day 6
Population: The evaluable population included participants who received a dose of N. gonorrhoeae within 1 log10 of the intended dose, reached an objective study endpoint (urethral discharge or day 6), and had a valid competitive index (the competitive index could not be calculated for participant who had a negative urine culture result on the day of treatment).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mixed FA1090/FA7537 | 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 | 15.11 ratio |
Comparison: To assess whether the fitness of a given mutant is different than that of wild-type, the ratio of colony-forming units of the mutant strain was compared to those of the WT strain at the time of treatment and in the inoculum using a Wilcoxon Signed-Rank Test with a significance level of 0.025. CIs of participants in Mixed FA1090 + FA7537 group were compared to mean = 1.p-value: 0.23Sign test
Secondary
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.
Time frame: Day 2 through the day of treatment, up to Day 6
Population: The evaluable population included participants who received a dose of N. gonorrhoeae within 1 log10 of the intended dose and reached an objective study endpoint (urethral discharge or day 6).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mixed FA1090/FA7537 | Median Time From Inoculation to Treatment Among Infected Participants by Day 6, by Strain, in Non-competitive Infections | 3.0 days |
| Wild-type FA1090 | Median Time From Inoculation to Treatment Among Infected Participants by Day 6, by Strain, in Non-competitive Infections | 3.0 days |
Secondary
Proportion of Participants With Occurrence of Bacteriuria in Non-competitive Infections, by Strain
Bacteriuria is defined as Log10 cfu N. gonorrhoeae/mL urine sediment.
Time frame: Day of occurrence, any day between Day 2 and Day 6
Population: The evaluable population included participants who received a dose of N. gonorrhoeae within 1 log10 of the intended dose and reached an objective study endpoint (urethral discharge or day 6).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mixed FA1090/FA7537 | Proportion of Participants With Occurrence of Bacteriuria in Non-competitive Infections, by Strain | 0.86 proportion of participants |
| Wild-type FA1090 | Proportion of Participants With Occurrence of Bacteriuria in Non-competitive Infections, by Strain | 1.00 proportion of participants |
Secondary
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.
Time frame: Day of occurrence, any day between Day 2 and Day 6
Population: The evaluable population included participants who received a dose of N. gonorrhoeae within 1 log10 of the intended dose and reached an objective study endpoint (urethral discharge or day 6).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mixed FA1090/FA7537 | Proportion of Participants With Occurrence of Signs and Symptoms of Urethritis Attributable to Gonococcal Infection in Non-competitive Infections, by Strain | 1.00 proportion of participants |
| Wild-type FA1090 | Proportion of Participants With Occurrence of Signs and Symptoms of Urethritis Attributable to Gonococcal Infection in Non-competitive Infections, by Strain | 1.00 proportion of participants |
Secondary
Proportion of Participants With Occurrence of Urethritis in Non-competitive Infections
Urethritis is defined as \>= 5.8 Log10 WBC/mL urine sediment.
Time frame: Day of occurrence, any day between Day 2 and Day 6
Population: The evaluable population included participants who received a dose of N. gonorrhoeae within 1 log10 of the intended dose and reached an objective study endpoint (urethral discharge or day 6).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mixed FA1090/FA7537 | Proportion of Participants With Occurrence of Urethritis in Non-competitive Infections | 1.00 proportion of participants |
| Wild-type FA1090 | Proportion of Participants With Occurrence of Urethritis in Non-competitive Infections | 1.00 proportion of participants |