NGU: Doxycycline (Plus or Minus Tinidazole) Versus Azithromycin (Plus or Minus Tinidazole)

Study Overview
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Brief Summary
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This study will look at the safety, effectiveness, and tolerability of combination medications for the initial treatment of non-gonococcal urethritis (NGU). NGU is inflammation of the tube that carries urine from the bladder. NGU is caused by bacteria that may be passed from person to person during sex. This study will compare the 2 currently recommended NGU treatments, doxycycline and azithromycin, taken with tinidazole (another medication to treat certain sexually transmitted infections). Tinidazole used with doxycycline or azithromycin may cure NGU better than when doxycycline or azithromycin is used alone. Study participants will be 300 men ages 16-45 years with NGU attending sexually transmitted disease clinics in Birmingham, AL; New Orleans, LA; Durham, NC; and Baltimore, MD. Study participation will last 7 weeks and involve 3 visits. At each visit, participants will provide a urine sample, have 2 urethral swabs, and have their urethra checked for discharge indicating infection.

Detailed Description
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This study represents a clinical evaluation of the use of combination therapy for the initial treatment of non-gonococcal urethritis (NGU). This study will provide more current data on the comparison of cure rates between the 2 currently recommended therapies for NGU, doxycycline and azithromycin. Emerging clinical data has suggested that the latter may have become more efficacious for NGU as it is more effective in eradicating Mycoplasma (M.) genitalium from the genital tract than the former. Only in vitro data, limited as it is, suggests that doxycycline should be active against M. genitalium. The researchers hypothesize that cure rates for NGU will be significantly improved for both doxycycline and azithromycin using combination therapy with tinidazole. Important safety and tolerability data will be collected with regards to the use of combination therapy. Additionally, the study will provide data on the prevalence of the targeted pathogens in 4 geographic areas and on characteristics of men with NGU that may help to target populations who would benefit the most from combination therapy. The researchers hypothesize that currently recommended initial therapies for NGU are inadequate in at least certain populations due to lack of coverage for Trichomonas (T.) vaginalis. The researchers further hypothesize that between the 2 currently recommended regimens, azithromycin will result in a greater number of cures than doxycycline due to its greater efficacy in M. genitalium infected men. The primary study objectives are to: compare the clinical cure rates of doxycycline versus doxycycline with tinidazole; and azithromycin versus azithromycin with tinidazole for the treatment of NGU; and to evaluate the safety and tolerability of doxycycline/tinidazole and azithromycin/tinidazole in the treatment of NGU. Secondary study objectives are to: evaluate microbiological cure of Chlamydia (C.) trachomatis, T. vaginalis, M. genitalium in men treated with doxycycline versus doxycycline with tinidazole; and azithromycin versus azithromycin with tinidazole. Analysis will also include: (doxycycline plus doxycycline/tinidazole) versus (azithromycin plus azithromycin/tinidazole); for the clinical cure rates, analysis will also include: (doxycycline plus doxycycline/tinidazole) versus (azithromycin plus azithromycin/tinidazole); determine the prevalence of C. trachomatis, T. vaginalis, and M. genitalium in the study population of men with non-gonococcal urethritis; determine clinical, behavioral, and demographic predictors of the above organisms in men with non-gonococcal urethritis; and collect specimens for future studies to determine the role of unique and novel pathogens in the etiology of non-gonococcal urethritis. Outcome measures include clinical failure, clinical cure, microbiological cure, and unevaluable cure assessed at the first and second follow-up visits. Study participants will include 300 men ages 16-45 years with NGU attending sexually transmitted disease clinics in Birmingham, AL; New Orleans, LA; Durham, NC; and Baltimore, MD. Subjects will be randomly assigned to 1 of 4 active treatment arms: 75 subjects doxycycline; 75 subjects doxycycline plus tinidazole; 75 subjects azithromycin; and 75 subjects azithromycin plus tinidazole.

Official Title
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Phase II Randomized, Placebo-Controlled Double-Blind 4-Arm Trial for the Treatment of Non-Gonococcal Urethritis (NGU): Doxycycline (Plus or Minus Tinidazole) Versus Azithromycin (Plus or Minus Tinidazole)

Conditions
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Urethritis

Intervention / Treatment
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* Drug: Tinidazole
* Other: Placebo
* Drug: Doxycycline
* Drug: Azithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, 16 to 45 years old. Symptoms of non-gonococcal urethritis (NGU), including urethral discharge and/or dysuria for less than or equal to 14 days, or urethral discharge on exam. Urethral smear with greater than or equal to 5 polymorphonuclear leukocytes (PMNs) per 3-5 oil immersion fields. Willing to abstain from sexual intercourse or use condoms during the study. Willingness to provide written consent. Exclusion Criteria: Presence of gonorrhea at baseline visit. History of recurrent non-gonococcal urethritis (NGU) (3 or more episodes in the prior year) or history of recent NGU (within past 30 days). Signs or symptoms of epididymitis or prostatitis. Known allergy to or intolerance of tinidazole, tetracyclines, macrolides or metronidazole. History of photosensitivity related to doxycycline use. Received systemic antibiotics within 30 days of study enrollment. Unwillingness to abstain from alcohol for 24 hours after enrollment. Serious underlying infection, including known HIV or other primary or secondary immunosuppression. Concomitant infection, which requires antimicrobial therapy. History of mental illness, which would preclude responsible participation in the study. Current drug abuse that might affect ability to follow the protocol. Previously enrolled in this study. Men who have sex with men, due to different microbiology of NGU. Voided within the previous hour. Ingested alcohol within the past 8 hours. Subject requires concurrent lithium, anticoagulation therapy, or antabuse.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxycycline<br>Doxycycline 100 mg orally twice daily (2 pills/day = 200 mg/day) for 7 days plus placebo azithromycin orally single dose and placebo tinidazole. | Other: Placebo<br>* Placebo capsule will be filled with lactose only and be identical in appearance to the capsule of Azithromycin, Tinidazole, Doxycycline.<br>Drug: Doxycycline<br>* 100 mg orally, twice daily for 7 days.<br>|
| Experimental: Doxycycline + Tinidazole<br>Doxycycline 100 mg orally twice daily for 7 days plus placebo azithromycin single dose plus tinidazole 2 gm orally single dose (4 tablets at 500 mg each). | Drug: Tinidazole<br>* 2 gm single dose (4 tablets orally at 500 mg each).<br>Other: Placebo<br>* Placebo capsule will be filled with lactose only and be identical in appearance to the capsule of Azithromycin, Tinidazole, Doxycycline.<br>Drug: Doxycycline<br>* 100 mg orally, twice daily for 7 days.<br>|
| Experimental: Azithromycin<br>Azithromycin 1 gram (gm) orally single dose (2 tablets at 500 milligrams (mg) each) plus doxycycline placebo twice daily for 7 days plus tinidazole placebo single dose. | Other: Placebo<br>* Placebo capsule will be filled with lactose only and be identical in appearance to the capsule of Azithromycin, Tinidazole, Doxycycline.<br>Drug: Azithromycin<br>* 1 gram (gm) (2 tablets orally at 500 milligrams (mg) each).<br>|
| Experimental: Azithromycin + Tinidazole<br>Azithromycin 1 gm orally single dose (2 tablets at 500 mg each) plus doxycycline placebo twice daily for 7 days plus tinidazole single dose (4 tablets at 500 mg each). | Drug: Tinidazole<br>* 2 gm single dose (4 tablets orally at 500 mg each).<br>Other: Placebo<br>* Placebo capsule will be filled with lactose only and be identical in appearance to the capsule of Azithromycin, Tinidazole, Doxycycline.<br>Drug: Azithromycin<br>* 1 gram (gm) (2 tablets orally at 500 milligrams (mg) each).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Doxycycline/Tinidazole and Azithromycin/Tinidazole: Number of Participants Reporting Nausea | At all study visits, unsolicited adverse events were recorded. Nausea, Vomiting, Abdominal pain, and Diarrhea were recorded using National Cancer Institute Common Toxicity Criteria (Version 3.0). | First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 
| Safety and Tolerability of Doxycycline/Tinidazole and Azithromycin/Tinidazole: Number of Participants Reporting Vomiting | At all study visits, unsolicited adverse events were recorded. Nausea, Vomiting, Abdominal pain, and Diarrhea were recorded using National Cancer Institute Common Toxicity Criteria (Version 3.0). | First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 
| Safety and Tolerability of Doxycycline/Tinidazole and Azithromycin/Tinidazole: Number of Participants Reporting Stomach Upset | At all study visits, unsolicited adverse events were recorded. | First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 
| Safety and Tolerability of Doxycycline/Tinidazole and Azithromycin/Tinidazole: Number of Participants Reporting of Abdominal Pain | At all study visits, unsolicited adverse events were recorded. Nausea, Vomiting, Abdominal pain, and Diarrhea were recorded using National Cancer Institute Common Toxicity Criteria (Version 3.0). | First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 
| Safety and Tolerability of Doxycycline/Tinidazole and Azithromycin/Tinidazole: Number of Participants Reporting Diarrhea | At all study visits, unsolicited adverse events were recorded. Nausea, Vomiting, Abdominal pain, and Diarrhea were recorded using National Cancer Institute Common Toxicity Criteria (Version 3.0). | First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 
| Percentage of Participants Achieving Clinical Cure of Non-gonococcal Urethritis (NGU) With Doxycycline Versus Doxycycline With Tinidazole; and Azithromycin Versus Azithromycin With Tinidazole | Clinical Cure of NGU: Did not meet criteria for clinical failure at last evaluable follow-up visit. Clinical Failure at first follow-up: [Persistent symptoms AND >= 5 polymorphonuclear leukocytes (PMNs) per 3-5 oil immersion fields (regardless of urethral discharge)] OR Persistent urethral discharge on exam (regardless of symptoms or number of PMNs). Clinical Failure at second follow-up: >= 5 PMNs per 3-5 oil immersion fields (regardless of symptoms or presence of urethral discharge) OR Persistent urethral discharge on exam (regardless of symptoms or number of PMNs) | First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Clinical Cure of NGU With (Doxycycline Plus Doxycycline/Tinidazole) Versus (Azithromycin Plus Azithromycin/Tinidazole) | Clinical Cure of NGU: Did not meet criteria for clinical failure at last evaluable follow-up visit. Clinical Failure at first follow-up: [Persistent symptoms AND >= 5 PMNs per 3-5 oil immersion fields (regardless of urethral discharge)] OR Persistent urethral discharge on exam (regardless of symptoms or number of PMNs). Clinical Failure at second follow-up: >= 5 PMNs per 3-5 oil immersion fields (regardless of symptoms or presence of urethral discharge) OR Persistent urethral discharge on exam (regardless of symptoms or number of PMNs) | First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 
| Percentage of Participants Achieving Microbiological Cure of Chlamydia Trachomatis With Doxycycline Versus Doxycycline With Tinidazole; and Azithromycin Versus Azithromycin With Tinidazole | Microbiological cure of Chlamydia trachomatis refers to the percentage of men with NGU who were negative for Chlamydia trachomatis at the last available result and had been positive for Chlamydia trachomatis at baseline. | First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 
| Percentage of Participants Achieving Microbiological Cure of Trichomonas Vaginalis With Doxycycline Versus Doxycycline With Tinidazole; and Azithromycin Versus Azithromycin With Tinidazole | Microbiological cure of Trichomonas vaginalis refers to the percentage of men with NGU who were negative for Trichomonas vaginalis (swab and urine specimens) at the last available result and had been positive for Trichomonas vaginalis at baseline (swab or urine specimen). | First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 
| Percentage of Participants Achieving Microbiological Cure of Mycoplasma Genitalium With Doxycycline Versus Doxycycline With Tinidazole; and Azithromycin Versus Azithromycin With Tinidazole | Microbiological Cure of Mycoplasma Genitalium refers to the percentage of men with NGU who were negative for Mycoplasma Genitalium at the last available result and had been positive for Mycoplasma Genitalium at baseline. | First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 
| Prevalence of Chlamydia Trachomatis in Men With Non-gonococcal Urethritis | Percentage of men with non-gonococcal urethritis that had a positive result for Chlamydia trachomatis at baseline (enrollment) | Baseline (enrollment visit) | 
| Prevalence of Trichomonas Vaginalis (Swab or Urine Specimen) in Men With Non-gonococcal Urethritis | Percentage of men with non-gonococcal urethritis that had a positive result for Trichomonas vaginalis from a urethral swab or urine specimen at baseline (enrollment) | Baseline (enrollment visit) | 
| Prevalence of Mycoplasma Genitalium in Men With Non-gonococcal Urethritis | Percentage of men with non-gonococcal urethritis that had a positive result for Mycoplasma genitalium at baseline (enrollment) | Baseline (enrollment) | 
| Clinical, Behavioral, and Demographic Predictors of Chlamydia Trachomatis in Men With Non-gonococcal Urethritis | Clinical, behavioral, and demographic variables considered were discharge amount and appearance; condom use last sex; new recent partner; number of partners and new partners in last 30 days as well as last 3 months; number of times vaginal sex, oral sex, or anal sex in past 30 days; always/almost always used condom in last 3 months. | Baseline (enrollment visit) | 
| Clinical, Behavioral, and Demographic Predictors of Trichomonas Vaginalis in Men With Non-gonococcal Urethritis | Trichomonas vaginalis was determined from urethral swab or urine specimen. Clinical, behavioral, and demographic predictors considered included discharge amount and appearance; condom use last sex; new recent partner; number of partners and new partners in last 30 days and last 3 months; number of times vaginal sex, oral sex, or anal sex in last 30 days; always/almost always used condom in last 3 months. | Baseline (enrollment visit) | 
| Clinical, Behavioral, and Demographic Predictors of Mycoplasma Genitalium in Men With Non-gonococcal Urethritis | Logistic multiple regression with independent variable selection based on single variable models with p<0.10. Participants positive at enrollment for Mycoplasma genitalium from urine specimen. Potential variables: discharge amount and appearance; condom use last sex; new recent partner, number of partners and new partners in last 30 days and last 3 months; number of times vaginal sex, oral sex, or anal sex in last 30 days; always/almost always used condom last 3 months. | Baseline (enrollment visit) | 
| Specimens for Future Studies to Determine the Role of Unique and Novel Pathogens in the Etiology of Non-gonococcal Urethritis | Urethral swabs and urine specimens collected at each study visit for future studies to determine the role of unique and novel pathogens in the etiology of non-gonococcal urethritis | Baseline (enrollment); First follow-up visit (Day 15-19), second follow-up visit (Day 35-45) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-gonococcal urethritis, doxycycline, azithromycin, sexually transmitted, tinidazole