Efficacy of Combination Therapies for Gonorrhea Treatment

Randomized Clinical Trial Evaluating the Efficacy of Gentamicin/Azithromycin and Gemifloxacin/Azithromycin Combination Therapies as an Alternative Regimen for Uncomplicated Urogenital Gonorrhea

The purpose of this study is to learn how to better treat gonorrhea infections. Gonorrhea is a sexually transmitted disease (STD) that is usually cured with a single antibiotic. However, some gonorrhea is not cured with a single antibiotic. The study will look at how well treating gonorrhea with 2 antibiotics works. Participants will be assigned to 1 of 2 treatment groups each receiving a combination of 2 antibiotics. Sites in the United States will recruit 500 male and female participants. Participants must be 15 to 60 years old, in good health and identified in participating sexually transmitted disease clinics as having uncomplicated cervical or urethral gonorrhea. Procedures include collection of current symptoms, medical and sexual history, sexual orientation, vital signs, height, weight, cervical/urethral cultures and clinical examinations. Volunteers will be involved for about 17 days.

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

Gentamicin 240 mg intramuscular (IM) one time for patients greater than 45 kg or 5 mg/kg IM one time for patients less than or equal to 45 kg plus azithromycin 2 gm by mouth one time.

Fixed dose of 240 mg intramuscular one time for patients >45 kg and a 5 mg/kg dose for patients less than or equal to 45 kg based on their measured weight in clinic. Most patients will require 2 injections of gentamicin in separate large muscle groups.

Microbiological Efficacy of Gentamicin and Azithromycin for the Treatment of Uncomplicated Gonococcal Infection

Percentage of enrollees negative by culture at cervix/urethra 10-17 days after treatment, regardless of history of re-exposure, among those with positive gonococcal cultures at enrollment (microbiological cure)

Microbiological Efficacy of Gemifloxacin and Azithromycin for the Treatment of Uncomplicated Gonococcal Infection

Percentage of enrollees negative by culture at cervix/urethra 10-17 days after treatment, regardless of history of re-exposure, among those with positive gonococcal cultures at enrollment (microbiological cure)

Number of enrollees with positive rectal culture at enrollment who have negative culture 10-17 days after treatment

Number of enrollees with positive pharyngeal culture at enrollment who have negative culture 10-17 days after treatment

For treatment failures (i.e., participants with positive culture at cervix/urethra 10-17 days after treatment), the minimum inhibitory concentrations for various antimicrobial agents (Azithromycin, Cefixime, Ceftriaxone, Ciprofloxacin, Gemifloxacin, Gentamicin, Penicillin, Tetracycline).

For treatment failures (i.e., participants with positive culture at cervix/urethra 10-17 days after treatment), number participants with clinical symptoms (vaginal/urethral discharge, dysuria, dyspareunia) at 10-17 days.

Number of participants whose gonorrhea-related symptoms (e.g. vaginal/urethral discharge, dysuria, dyspareunia) present at enrollment has resolved by visit 2.

Minimum inhibitory concentration (micrograms/milliliter) of pretreatment gonorrhea isolates collected from participants

Number of treated participants experiencing mild, moderate, severe, or life-threatening adverse events (AEs) either temporarily associated or not associated with study product.

Inclusion Criteria: Male or female from 15 - 60 years old. Is either: 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. Urethral or cervical gram stain demonstrating gram negative intracellular diplococci and leukocytes. 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

Kirkcaldy RD, Weinstock HS, Moore PC, Philip SS, Wiesenfeld HC, Papp JR, Kerndt PR, Johnson S, Ghanem KG, Hook EW 3rd. The efficacy and safety of gentamicin plus azithromycin and gemifloxacin plus azithromycin as treatment of uncomplicated gonorrhea. Clin Infect Dis. 2014 Oct 15;59(8):1083-91. doi: 10.1093/cid/ciu521. Epub 2014 Jul 16.