Experts Collaborate to Design Thorough and Effective Future Trials
On February 5-6, 2019, NIAID and the Sexually Transmitted Infection (STI) Clinical Trials Group co-hosted a workshop entitled “Considerations for Optimal Trial Design for Evaluation of Antimicrobials for Urogenital Gonorrhea” in Rockville, Maryland. This meeting convened selected U.S. and international academic, governmental, and not-for-profit organization experts from within and outside the field of STI research to discuss current challenges in gonorrhea antimicrobial therapy development and to identify improved designs for effective future trials. Gonorrhea is the second most common notifiable sexually transmitted disease in the United States, and CDC reports that the rate of reported cases of gonorrhea has increased each year since 2013. Unfortunately, the gonococcus has developed antimicrobial resistance to each successive generation of recommended therapy quite rapidly, and the pipeline for new drugs is limited. Gonorrhea is typically treated with single dose or short course antimicrobial therapy in public health settings, and evaluation of new antimicrobials for gonorrhea therapy has proven challenging.
Gonorrhea is a sexually transmitted infection caused by the bacteria Neisseria gonorrhoeae (Gc). The most common sites of infection are urogenital (urethral in men and cervical in women), but Gc is known to manifest as rectal, pharyngeal, and conjunctival infections as well. Untreated infection in men can lead to epididymitis, urethral stricture, and infertility, and untreated infection in women may lead to pelvic inflammatory disease (PID), which can cause infertility and life-threatening ectopic pregnancy, endometritis, salpingitis, and tubo-ovarian abscesses. Additionally, gonorrhea has been shown to increase HIV transmission.
There is no vaccine available that protects against Gc infections, which means that controlling the spread of infection relies on effective treatment of gonorrhea. The current recommendation for treatment of uncomplicated gonorrhea in the US and many other countries is “dual therapy” with injectable ceftriaxone and oral azithromycin. Dual-antimicrobial regimens are not feasible for resource-poor settings, and the evolution and spread of antimicrobial resistance to the medications recommended for treatment necessitates novel drugs to be evaluated.
Current guidelines for evaluation and consideration of new drugs for gonorrhea treatment have limited the drug development pipeline. Developing statistically robust trials proves difficult with a “dual therapy” comparator that includes a highly effective drug (ceftriaxone) as well as a long acting drug (azithromycin). Furthermore, the populations at highest risk for gonorrhea— adolescents, women at risk, and men who have sex with men— are hard to enroll and follow up with in trials. While culture is the current gold standard for gonorrhea diagnosis and antimicrobial resistance testing, gonorrhea culture is technically demanding and can only be done in limited settings. Thus, nucleic acid amplification tests (NAATs) are becoming the more preferred method to detect Neisseria gonorrhoeae even though they cannot be used currently to determine antimicrobial resistance, and they can be falsely positive for two to three weeks after treatment.
Attendees noted that although established guidelines dictate that treatment efficacy should be the primary endpoint to measure, there may be value in adding in consideration of combined outcomes that include quality of life (QOL) and safety measures, for example. Attendees also considered the possibility of alternative study designs, such as use of master protocols for studies with multiple study arms for different drugs and the seamless linking of phase 2 and 3 trials, that could make trials more feasible and less costly.
Another major concern brought up during the consultation was the lack of microbiological evidence behind the theory that using dual therapy to treat gonorrheal infections would slow antibiotic resistance, and there was support by attendees for the upcoming CDC treatment guidelines to develop the next generation of guideline development on only high quality evidence related to the treatment of gonorrhea (and not assume co-infection with chlamydia in all individuals). Workshop participants also emphasized the importance of increased pre-clinical work in either the murine or hollow fiber models before moving to clinical trials, and in particular improved understanding of a broader array of pharmacokinetic and pharmacodynamic measures, such as tissue levels. Furthermore, participants felt that multiple dose therapy should be considered where pharmacokinetic data support it. It was generally agreed upon among the experts that use of a single comparator rather than a dual comparator was critical for understanding the relative efficacy of new treatment regimens.
Other suggestions from the participants related to how to facilitate or improve enrollment in studies of urogenital gonorrhea. Maximizing efforts to minimize loss to follow up, tailoring contraceptive requirements to specific risk of each study, and ensuring that clinical trials are adolescent-friendly, were just some of the suggestions that arose during the workshop.
NIAID plans to use the input from this meeting to guide development of future trials evaluating therapeutics for urogenital gonorrhea to ensure that sufficient alternatives for effective treatment of gonorrhea can stay ahead of evolving antimicrobial resistance.