Zoliflodacin is an oral antibiotic with a novel mode of action distinct from quinolones. The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin in a phase 2 study conducted in the U.S.1 Zoliflodacin offers many of the WHO preferred characteristics for gonorrhoea therapy, including single dose therapy, low rate of side effects, and both urogenital and extragenital site efficacy 2.
To further development of zoliflodacin, the Global Antibiotic Research and Development Partnership (GARDP), a Swiss-based non-profit foundation, has partnered with Entasis Therapeutics, Inc., the World Health Organization, and the U.S. National Institute of Allergy and Infectious Diseases (NIAID), and is sponsoring and managing a multinational phase 3 randomized clinical trial of zoliflodacin for gonorrhoea therapy (NCT03959527).
Removing the requirement for in-person visits at day 30 allowed us to decrease the risk of exposure to COVID-19 for both participants and site study staff.
This single pivotal trial is a multi-center, open-label, randomized, controlled, non-inferiority, phase 3 trial evaluating the safety and efficacy of a 3 g oral dose of zoliflodacin, compared to a single intra-muscular dose of 500 mg ceftriaxone combined with a single oral dose of 1 g azithromycin, which is standard of care for the treatment of uncomplicated Neisseria gonorrhoeae (NG) infection.
The study aims to enroll at least 600 microbiologically evaluable patients and includes three clinical visits: Enrolment and Treatment (day 1), Test-of-Cure (ToC, day 7) with microbiological testing as the primary endpoint assessment, and Follow-Up (day 30) to confirm safety and sustained eradication of pathogens. Recruitment of participants is from 14 sites located in the USA, South Africa, Netherlands, and Thailand.
The overview below is from the sponsor (GARDP) medical monitoring team, a moderator between clinical and protocol necessities, dedicated to participants’ safety as well as study objectives.
Stage 1: “First” lockdown and mitigation of missed visits
At the beginning of the COVID-19 pandemic, six sites were activated in the US and preparations to activate sites in the Netherlands, Thailand and South Africa were progressing to plan. We began to assess the possible impact of the emerging pandemic on the conduct of the trial based on the following criteria:
- Inability for local study staff to work (both site and sponsor)
- Risk to clinical trial patients outweighing the benefits of enrolling in the study
- Issues with data integrity
- Impact on lab capacity
- Issues with drug supply or equipment
- Any impact of study continuation on public health resources
Upon receipt of information from site investigators regarding local lockdowns, GARDP, in conjunction with the study sites, decided to temporarily halt patient enrolment, informing the FDA and all ethics committees.
At this stage, all participants who had been enrolled and treated in the trial had attended their day 7 ToC visits. Clinical and microbiological evaluations for the primary endpoint were therefore unaffected. For the protocol-specified day 30 follow-up visit, however, the risks and benefits of substituting an in-person clinic visit (enabling collection of microbiological and safety blood samples) with a remote telephonic follow-up, were carefully evaluated.
The safety of participants and staff is not the only consideration in the context of this pandemic. Key aspects related to data quality and laboratory procedures are also impacted.
Eradication rates are typically very high in NG studies and safety laboratory abnormalities are uncommon since most participants are young, otherwise healthy individuals. However, our trial also enrolls participants who have comorbidities such as HIV co-infection that may place them at higher risk for COVID-19.
To inform the decision whether to persist with in-person microbiological and safety laboratory testing on day 30, we reviewed blinded individual data from the ToC visit for these patients. All patients had been culture-negative at test-of-cure with no evidence of significant safety laboratory abnormalities. A decision was therefore made in accordance with early FDA and EMA COVID-19 guidance documents to conduct remote, telephonic follow-ups in lieu of in-person visits for day 30. During the day 30 calls, no participants reported new clinical NG symptoms nor any other conditions which would have required in-person testing or evaluation. Although safety laboratory assessments were not conducted, other relevant day 30 data were captured in rapidly modified electronic case record forms, keeping those patients eligible for the primary endpoint assessment population. This approach was recorded in the trial master file as a planned protocol deviation. Removing the requirement for in-person visits at day 30 allowed us to decrease the risk of exposure to COVID-19 for both participants and site study staff.
Stage 2: Considerations for study amendments and adaptations
Since prospectively approving protocol deviations (“prospective waivers”) remain prohibited in pivotal studies 3, 4, the inclusion of alternative screening and follow-up procedures, or other substantially different options for newly enrolled patients would have required amendment(s) to the protocol and, in particular, the informed consent form. COVID-19-specific regulatory guidance by FDA and EMA offer a streamlined filing process, but we elected not to amend the protocol to specifically address COVID-19 related issues. We decided, post consultation with investigators, to focus on a “re-launch strategy” with sites based on an ongoing evaluation of how to conduct the study in a COVID-19 pandemic. In particular, certain procedural adaptations have been permitted to reduce the risk of COVID-19 transmission, for example during collection of pharyngeal samples.
The term “COVID-19” or “risk of respiratory infections” will not be specifically addressed in the current protocol. Activities related to patient screening for COVID-19 remain site-specific and are evolving over time, with the medical monitoring team facilitating exchange of best-practice guidance. Investigators are encouraged to interpret the exclusion criterion, “individuals whom, in the judgement of the investigator, are unlikely or unable to comply with this trial protocol” (a typical element of phase 3 pivotal protocols), in relation to whether or not individual participant enrolment is appropriate in their respective pandemic environment.
Notwithstanding the enormous challenges facing researchers during this pandemic, we believe that high quality global research continues to be possible. Adaptation to changing environments is an evolutionary necessity and continuing access to gonorrhoea diagnosis and treatment must continue to remain a global health priority.
The safety of participants and staff is not the only consideration in the context of this pandemic. Key aspects related to data quality and laboratory procedures are also impacted. Travel restrictions pose a challenge for on-site monitoring visits, resulting in a potential for incomplete study data. Closures of laboratories, especially when on university campuses, or re-purposing of laboratories for COVID-19 related assays only, is commonplace and can result in delays with opening or re-activation of sites. National and international flight limitations and transportation challenges also impact sample shipment.
Stage 3 (ongoing): Re-launch criteria and launch around the globe in new-normal times
Despite the ongoing COVID-19 pandemic, the need for new antibiotics for the treatment of drug-resistant gonorrhoea persists. Our challenge is to facilitate continued recruitment in the zoliflodacin trial while limiting risks for both trial personnel and participants and ensuring data integrity. To mitigate risk, sites have implemented local guidance. Although these vary, typical elements include pre-screening measures prior to clinic visits (recent exposure, respiratory symptoms, or testing at entry – which is least practical) and interaction measures (distancing, phone interactions, protective equipment). As the trial sponsor, GARDP approves these in conjunction with site teams prior to each site resuming and/or starting enrolment.
Preparations in Thailand, where COVID-19 infection rates are low, are currently progressing well for site activation in the coming months, and sites in South Africa will be activated when site staff and laboratories are able to resume clinical research once COVID-19 infection rates decrease. Notwithstanding the enormous challenges facing researchers during this pandemic, we believe that high quality global research continues to be possible. Adaptation to changing environments is an evolutionary necessity and continuing access to gonorrhoea diagnosis and treatment must continue to remain a global health priority.
Creation and launch of a phase 3 programme is a huge team effort requiring many specialties and highly motivated individuals working together. The zoliflodacin phase 3 study past and present team also includes: Emilie Alirol, Jessica Renaux, Karin Hergarden, Manon Manuelli, Anthony Simon, Stephen Robinson, Edward Mukwaya (South Africa), Melanie Mackay (South Africa), Sarah Cohen (South Africa), Nauwarat Imlimtharn (Thailand), Varalakshmi Elango, Cherine Bajjali and Carmen Au. Also, we recognize the contribution of our partners at Entasis.