Introduction and Background of the Project

Introduction

Mycetoma affects the poorest populations in the most remote areas, both men and women. Those that work or travel barefoot are the most at risk: field labourers and herders. Mycetoma is a chronic infection of the subcutaneous tissue. It is a disfiguring disease reported in a usually young rural population in (sub)tropical regions (the “mycetoma belt, between latitudes 150 South and 300 North). The disease seems to be most prevalent in Sudan. It may be caused by bacteria (actinomycetoma), for which antibiotics are effective; or by fungi (eumycetoma) for which current antifungal treatments are long, toxic, ineffective, and expensive. After the causative agent of mycetoma enters the body, the disease starts as a small lump under the skin with painless swelling. This slow-growing disease initially causes little discomfort and consequently people delay seeking treatment until the disease has reached a more advanced stage with severe morbidity, making treatment more difficult. The infection can spread to other parts of the body and can be fatal. The only available treatment is itraconazole which has poor documented efficacy after twice a day dosing for a minimal 12 months. Moreover, the price of itraconazole is prohibitive with a cost of treatment of 2,160 USD a year. This figure needs to be put in perspective in countries like Sudan where people in poor communities earn as little as 4,500 USD a year, thus creating an unbearable burden for them. As a result of poor drug efficacy and compliance to treatment, recurrence is common; amputations are often necessary, adding to the severe morbidity and stigma.

Fosravuconazole, an azole-class antifungal drug discovered by the Japanese pharmaceutical company Eisai, is a promising new drug for mycetoma. It has shown to have strong antifungal activities against mycetoma in the laboratory.

Project objective

DNDi facilitated the in vitro testing of ravuconazole, the active form of fosravuconazole, in mycetoma. Ravuconazole has shown to have the most potent in vitro activity against the most common of the causative agents of eumycetoma, Madurella mycetomatis. Eumycetoma is the fungal form of mycetoma. In addition, the drug has a favourable safety profile, its toxicity is low and it is administered once weekly. The medium-term objective of DNDi is to deliver fosravuconazole, as a safe, effective antifungal agent, appropriate for use in rural settings for the treatment of patients with eumycetoma. In this respect, the objective of the project is to conduct and complete the first Phase II Proof of Concept study to assess fosravuconazole.

Project design

DNDi privileges a scientific short term approach to test the efficacy of fosravuconazole. A double-blind, comparative, randomized controlled trial in 138 adult patients in Sudan, will be conducted in the WHO Collaborating Centre on Mycetoma in Khartoum, in collaboration with other partners. We will study the efficacy of fosravuconazole in patients with moderate mycetoma lesions in comparison with the current treatment, itraconazole. The primary objective of this study is to demonstrate the superiority of fosravuconazole over itraconazole after 12 months’ treatment. Two different doses of fosravuconazole will be tested (200 mg and 300 mg weekly dose) and an interim analysis when 28 patients per arm reach 3 months will decide which of the two test arms should be continued based on efficacy and safety. All patients will have surgical removal of the remaining lesion at 6 months after which antifungal treatment will continue for another 6 months. Microbiological diagnosis at baseline, follow-up and end-of-treatment will be done by PCR; the causative agent will also be cultured and tested for antifungal resistance before and after treatment. Drug levels will be measured. DNDi is committed to identify and work with partners having interest in developing diagnostics or conducting field mission in order to identify patients at an early stage and improve recruitment. Transfer of knowledge and training are important components of the study.

How can your partnership (project) address global health challenges?

Mycetoma has only been included to the World Health Organization’s official list of Neglected Tropical Diseases in May 2016, though cases date back more than 300 years. Eumycetoma patients have received little attention and virtually no research and development has addressed their needs to date. There are major knowledge gaps about mycetoma from transmission, to prevalence, to route of infection and to susceptibility and therefore the global burden of mycetoma cannot be determined accurately. However, the individual socioeconomic impact and stigma are clear. This is the first randomized clinical trial ever conducted in mycetoma which will hopefully lead to further studies using the capacity built in this trial, as well as elsewhere. It will provide a reference for future clinical trials. It will also investigate a potential new standard of care able to answer the problematics of a very long treatment period (at least one year), partial cure, serious side effects and subjects who drop out of follow-up with resultant high recurrence rates and subsequent amputations. The prolonged use of the currently available drugs proved to be not affordable and thus not cost effective by both the health authorities and patients. The outcome of the study will therefore form an important pillar of local and regional control programs. Mycetoma has a particular multiplier effect in impoverished communities with patients being primary providers for their families unable to work and students not able to attend school resulting in carrying on the circle of poverty. Most of the cases reported were from Mexico, Sudan and India. Globally, mycetoma is not a notifiable disease and is not monitored in any national surveillance systems. More accurate surveillance and burden of disease data are therefore essential in order to evaluate its significance as a public health problem.     

What sort of innovation are you bringing in your project?

This project brings innovation in a number of ways.

DNDi and Eisai are looking at improving the standard of care for patients with eumycetoma. 

This is the first randomized clinical trial ever conducted in eumycetoma. Most studies were in limited numbers of patients with varying duration of treatment and follow-up, with non-standardized outcome measures. It will hopefully lead to further studies using the capacity built in this trial, as well as elsewhere and provide a reference for future clinical trials. We can argue that if the topic of the project: mycetoma can’t be described as an innovation in itself it is however a new subject being discussed at the global health level. The official inclusion of mycetoma on the WHO List of NTDs gave the disease the political support and the visibility needed to stimulate new initiatives to better describe the epidemiology, the risk factors for transmission, early and accurate identification of cases as well as new treatment strategies, aiming at the development of successful control programs. Early 2017, the WHO NTD Department has started to collect basic epidemiological data, and a roadmap for control of mycetoma is being discussed. A research network is expanding and includes, among other, the Erasmus Medical Center in Rotterdam, the Free University in Amsterdam in the Netherlands and Eisai Co., Ltd in Japan. A network of collaborators in all endemic areas is being established with the help of the WHO. Our partner in the project, the Mycetoma Research Center in Khartoum was recently recognized as a WHO Collaborative Center and provides clinical and laboratory services as well as health education and research.

Role and Responsibility of Each Partner

Eisai Co., Ltd. has developed fosravuconazole and will make the study drug available to DNDi. Eisai will also provide pharmacovigilance and technical support in clinical pharmacology throughout the project to DNDi. 

DNDi will coordinate the project, conduct the clinical trial, and will be responsible for data entry and data analysis to produce the clinical trial report. Both parties will review the data to produce the clinical trial report and provide insight in the drafting of the report.  Pertaining to decision-making procedures, there is a Joint Development Committee (JDC) in place which meets regularly. The purpose of the JDC is to review the progress and the results of the clinical trial, approve the protocols of the trial and propose modifications as deemed appropriate. DNDi is chair of the JDC and responsible for setting-up meetings– there are two permanent representatives from Eisai and DNDi and of such additional invited representatives. The JDC will make decisions by majority vote. In the case of a disagreement within the JDC, the issue will be brought to the senior executives of DNDi and Eisai to find a consensus.   

Final Report

1. Project objectives

Fosravuconazole, an oral azole-class antifungal drug discovered by Eisai Co., Ltd. (Eisai) and developed for patients with onychomycosis, is a promising new drug for mycetoma. It has shown to have the most potent in vitro activity against the most common of the causative agents of eumycetoma, Madurella mycetomatis. DNDi conducted the first-ever randomized, double-blind Phase II Proof of Concept study for eumycetoma in Sudan, in partnership with Eisai and the Mycetoma Research Center (MRC) in Khartoum, Sudan, to demonstrate safety and efficacy of fosravuconazole in comparison with the current treatment, itraconazole.

2. Project design

The trial assessed the safety and efficacy of fosravuconazole in patients with moderate mycetoma lesions in comparison with itraconazole after 12 months’ treatment. Two different doses of fosravuconazole were tested (200 mg and 300 mg weekly dose). All patients had surgical removal of the remaining lesion at 6 months, after which antifungal treatment continued for another 6 months. Microbiological diagnosis at baseline, and end-of-treatment was done by PCR. The causative agent was also cultured and tested for antifungal resistance before and after treatment. Drug levels in plasma were measured.

3. Results, lessons learned

Between 2017-2020, 104 patients have been recruited, and because of Covid-19 and subsequent lockdown(s) in Sudan, the trial was terminated early based on the recommendation by the Data Safety Monitoring Board and supported by DNDi Scientific Advisory Committee.

The results of the study showed that both drugs had similar efficacy rates. Fosravuconazole had an efficacy rate of 65.4% and 84.6% in the 300 mg arm and the 200 mg arm, respectively, while the itraconazole 400 mg arm had an efficacy rate of 80% in the per protocol population. The itraconazole efficacy rate was higher than expected based on historical case-report data. While the difference between these efficacy rates was not found to be statistically significant, fosravuconazole has significant advantages over itraconazole, the standard of care in Sudan. Only two pills of fosravuconazole need to be taken once a week, compared to four tablets per day for itraconazole. This will greatly improve adherence and convenience for patients. In addition to the only once-a-week dosing, fosravuconazole has no food effect, so patients do not have to worry about taking it before or after a meal. The drug also has minimal interactions with other medications, which is particularly important for the sub-Saharan population that may suffer from comorbidities like HIV or tuberculosis and may be taking multiple drug combinations.

Since recurrence in mycetoma is common, the observational long term post-treatment follow-up after end of clinical trial was also conducted to collect data on recurrence of eumycetoma lesions in participants who previously participated in the trial. Although it was not possible to follow-up all planned 75 patients due to the political situation in Sudan, this study, based on 51 patients enrolled, showed that the eumycetoma recurrence rates for participants previously treated with fosravuconazole 300 mg, fosravuconazole 200 mg and itraconazole 400 mg were numerically similar and low in this group of participants in Sudan. No serious adverse events were reported.