Efficacy of Combination Therapies for Gonorrhea Treatment

Infection with Neisseria (N.) gonorrhoeae carries a significant public health burden in the
United States (U.S.). Gonococcal infection can result in pelvic inflammatory disease (PID),
ectopic pregnancy, infertility, chronic pelvic pain, and increases the risk of transmission
and acquisition of human immunodeficiency virus (HIV). With over 350,000 cases of gonorrhea
reported each year, gonorrhea is the second most common notifiable condition. Furthermore,
it is estimated that case reports account for only half of the incident cases of gonorrhea
in the U.S. each year. Given that gonorrhea is a bacterial infection which causes symptoms
in approximately 90 percent of infected men and 50 percent of infected women, the most
critical aspect of reducing the public health burden of gonorrhea for affected populations
is provision of effective antimicrobial therapy. In order to identify treatment options for
patients with suspect or confirmed cephalosporin-resistant N. gonorrhoeae infection and
patients with severe cephalosporin hypersensitivity, this study plans to determine the
efficacy of each of 2 combination antimicrobial regimens for the treatment of uncomplicated
gonococcal infection. This study is a multicenter clinical trial of adult males and females
diagnosed with urethral or cervical gonococcal infection. Subjects will be enrolled and
randomized for treatment with either Regimen A: gentamicin 240 mg intramuscular (IM) one
time for patients >45 kg or 5 mg/kg IM one time for patients less than or equal to 45 kg
plus azithromycin 2 gm by mouth (PO) one time, or Regimen B: gemifloxacin 320 mg PO one time
plus azithromycin 2 gm PO one time. Investigators hypothesize that Regimen A will have a
clinical efficacy estimate that is greater than or equal to 95 percent as well as a lower,
one-sided 95 percent confidence interval (CI 95 percent) bound that is greater than or equal
to 90 percent. The identical hypothesis applies for Regimen B. It should be noted that this
is not a comparative trial between Regimen A and B, but rather a trial to establish efficacy
data for each of these two candidate regimens. The primary objective of this study is to
determine the microbiological efficacy of each of two combination antimicrobial regimens for
the treatment of uncomplicated gonococcal infection (i.e., non-systemic). Secondary
objectives of this study are to: assess the safety and tolerability of each candidate
regimen; assess the eradication of any rectal or pharyngeal gonococcal infection by each
regimen; determine the antimicrobial susceptibility profile of all gonococcal strains
isolated at the time of enrollment; determine the clinical and antimicrobial susceptibility
profile of all gonococcal strains isolated from patients who fail treatment; and assess the
efficacy of the candidate regimens on the resolution of symptoms and signs (clinical cure).
The primary efficacy analysis will be based on microbiological cure rate at end of trial
based on the modified intent-to-treat (MITT) and per protocol (PP) subsets. The number,
percent, and a 95 percent one-sided (lower) confidence interval of microbiological cure rate
successes and failures will be computed. Additional analyses will be conducted on the
following subsets: male, female, men who have sex with men (MSM) status, and subjects
denying anal, oral, or vaginal intercourse during the follow-up period. Secondary endpoints
will include: separate analyses of: safety and tolerability of each regimen; eradication of
rectal or pharyngeal infection; antimicrobial susceptibility profile of enrollment isolates;
clinical and antimicrobial susceptibility profile of treatment failures; and resolution of

Inclusion Criteria:

- Male or female from 15 - 60 years old.

- Is either:

1. Untreated male or female with urethral or cervical gonorrhea as determined by a
screening laboratory test [either Nucleic Acid Amplification Test (NAAT) or
culture] for Neisseria gonorrhoeae at a prior visit.

2. Urethral or cervical gram stain demonstrating gram negative intracellular
diplococci and leukocytes.

3. Untreated male or female who is a sexual contact (anal, oral, or vaginal) of an
individual with gonorrhea in the past 60 days.

- Willing to abstain from anal, oral, or vaginal sexual intercourse or use condoms
until follow up is completed.

- Willing to follow up from 10 to 17 days following enrollment.

- Willing to provide written consent.

- Able to swallow pills.

Exclusion Criteria:

- Known renal insufficiency from clinical history

- Known hepatic insufficiency from clinical history

- Known QT interval prolongation from clinical history

- Known neuromuscular disorder from clinical history (i.e., myasthenia gravis or
Parkinson's disease)

- Known rheumatoid arthritis or tendon disorders from clinical history

- Known kidney, heart, or lung transplants from clinical history

- Pregnant women (determined by positive urine pregnancy test)

- Breastfeeding women

- Known allergy or adverse reaction to macrolides, aminoglycosides, or quinolones

- Concomitant infection (besides chlamydia or bacterial vaginosis) which requires
systemic antibiotics

- Has received systemic or intravaginal antibiotics within 30 days of study enrollment

- Currently taking corticosteroid drugs or other immunosuppressive therapy

- Currently taking cardiac antiarrhythmia drugs

- Self report of or clinical diagnosis of abdominal pain, pelvic inflammatory disease
(PID), testicular pain, epididymitis, or disseminated gonococcal infection

- Self report of or clinical diagnosis of current genital ulcer (GU)

- In the judgment of the interviewer, has a medical condition or other factor that
might affect their ability to follow the protocol

- Previous enrollment in this study