Official Title: “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)”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: November 2009

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 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 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 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; 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 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. Subjects will be randomly assigned to 1 of 4 active treatment arms: doxycycline for 7 days plus placebo azithromycin single dose and placebo tinidazole; doxycycline for 7 days plus placebo azithromycin single dose plus tinidazole single dose; azithromycin single dose plus doxycycline placebo for 7 days plus tinidazole placebo single dose; or azithromycin single dose plus doxycycline placebo for 7 days plus tinidazole single dose.

Intervention(s) in this Clinical Trial

• Drug: Azithromycin
  • 1 gm (2 tablets PO at 500 mg each)
• Drug: Doxycycline
  • 100 mg PO BID for 7 days
• Drug: Placebo
  • Placebo azithromycin; placebo tinidazole; and doxycycline placebo.
• Drug: Tinidazole
  • 2 gm single dose (4 tablets PO at 500 mg each)

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Doxycycline 100 mg PO BID (2 pills/day = 200 mg/day) for 7 days plus placebo azithromycin PO single dose and placebo tinidazole.
• Experimental: 2
  • Doxycycline 100 mg PO BID for 7 days plus placebo azithromycin single dose plus tinidazole 2 gm PO single dose (4 tablets at 500 mg each).
• Experimental: 3
  • Azithromycin 1 gm PO single dose (2 tablets at 500 mg each) plus doxycycline placebo BID for 7 days plus tinidazole placebo single dose.
• Experimental: 4
  • Azithromycin 1 gm PO single dose (2 tablets at 500 mg each) plus doxycycline placebo BID for 7 days plus tinidazole placebo single dose.

Primary Measures

• Treatment: compare the clinical cure rates of doxycycline versus doxycycline with tinidazole; and azithromycin versus azithromycin with tinidazole.
  • Time Frame: First follow-up visit, second follow-up visit
    Safety Issue?: No
• Evaluate the safety and tolerability of doxycycline/tinidazole and azithromycin/tinidazole in the treatment of NGU.
  • Time Frame: Duration of study
    Safety Issue?: Yes

Secondary Measures

• Evaluate microbiological cure of C. trachomatis, T. vaginalis, and M. genitalium in men treated with doxycycline versus doxycycline with tinidazole; and azithromycin versus azithromycin with tinidazole.
  • Time Frame: First follow-up visit, second follow-up visit
    Safety Issue?: No
• Clinical cure rates, analysis will also include: (doxycycline plus doxycycline/tinidazole) versus (azithromycin plus azithromycin/tinidazole).
  • Time Frame: First follow-up visit, second follow-up visit
    Safety Issue?: No
• Prevalence of C. trachomatis, T. vaginalis, and M. genitalium in men with non-gonococcal urethritis; clinical, behavioral, and demographic predictors of C. trachomatis, T. vaginalis, and M. genitalium in men with non-gonococcal urethritis.
  • Time Frame: Duration of study
    Safety Issue?: No
• Collect specimens for future studies to determine the role of unique and novel pathogens in the etiology of non-gonococcal urethritis.
  • Time Frame: First follow-up visit, second follow-up visit
    Safety Issue?: No

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.
• 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.

Gender Eligibility for this Clinical Trial: Male

Minimum Age for this Clinical Trial: 16 Years

Maximum Age for this Clinical Trial: 45 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Overall Clinical Trial Officials and Contacts

Overall Contact: Joy Lewis (205) 996-2780 schwebke@uab.edu

Information obtained from ClinicalTrials.gov on August 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00322465

Study ID Number: 05-0120

ClinicalTrials.gov Identifier: NCT00322465

Health Authority: United States: Institutional Review Board