Proof-of-Concept Superiority Trial of Fosravuconazole Versus Itraconazole for Eumycetoma in Sudan
Proof-of-Concept Superiority Trial of Fosravuconazole Versus Itraconazole for Eumycetoma in Sudan
This study is a single-center, comparative, randomized, double-blind, parallel-group,
 active-controlled, clinical superiority trial of Fosravuconazole versus Itraconazole combined
 with surgery in subjects with eumycetoma in Sudan.

 There will be three arms in this study: The first arm will be Fosravuconazole 300 mg weekly,
 the second arm will have Fosravuconazole 200 mg weekly and the control arm is the standard
 treatment using itraconazole 400mg daily.

 At 3 months time-point, interim analysis will be done and one of the study arms will be
 dropped according to the drop-the-loser design, based on efficacy or toxicity.
Eumycetoma is a fungal disease caused by Madurella mycetomatis. The disease is chronic,
 granulomatous and inflammatory. It usually involves subcutaneous tissues and leads to masses
 and sinuses from which fungal grains are discharged. It is most probably introduced post
 trauma e.g. thorn prick. It is associated with major morbidity and can be disabling,
 disfiguring and highly stigmatizing. In advanced cases it may be fatal. Eumycetoma is most
 prevalent in what is known as mycetoma belt.

 Current treatment modalities for eumycetoma are disappointing. The response is characterized
 by low cure rates, high amputation rates, high up drop out from follow up and high recurrence
 rates. The available drugs for the treatment of eumycetoma are expensive, potentially toxic
 and require a long treatment period up to 12 months. By that time the mass is well
 encapsulated and is removed surgically. Despite prolonged medical treatment, the causative
 organisms are commonly found to still be viable and can be cultured from the surgical
 specimen.

 The objectives of this study are to determine the comparative efficacy, safety, and
 tolerability of Fosravuconazole versus itraconazole as first-line treatment for subjects with
 eumycetoma caused by Madurella mycetomatis. The primary end-point will be complete cure after
 12 months treatment as evidenced by clinical assessment showing absence of mycetoma mass with
 closure of sinuses and absent discharge, normal ultrasonic examination of the lesion, or the
 presence of fibrosis only associated with a negative fungal culture from a surgical biopsy
 from the former mycetoma site. The secondary endpoints are the outcome at 3-month's time
 point based on the same criteria as 12 month and/or treatment-related adverse events at the
 3- and 12-month visits. The study will also monitor plasma drug levels of ravuconazole and
 itraconazole that will be included in a logistic model with other clinical and laboratory
 parameters to predict outcome. In addition, immunological studies will be done to describe
 the developing or changing immune responses during treatment. Lastly, all strains collected
 will be cultured and typed and with assessment of antifungal resistance.

 This study is a single-center, comparative, randomized, double-blind, parallel-group,
 active-controlled, clinical superiority trial in subjects with eumycetoma requiring surgery.
 There will be three arms this study: The first arm will have Fosravuconazole 300 mg weekly
 and the second arm will have Fosravuconazole 200 mg weekly. Both arms will be evaluated at 3
 months. At this time-point, one of the study arms will be dropped according to the
 drop-the-loser design, based on efficacy or toxicity. The control arm is the standard
 treatment using itraconazole 400mg daily. Patients will receive treatment for one year. An
 interim analysis is planned after data has been accumulated for sample size of 28 for 3
 months end point.

 This study will be done at the Mycetoma Research Centre, Sudan when ethics and regulatory
 approvals are received. The study plans to recruit 138 subjects by the end of the trial. The
 main inclusion criteria are subjects who provide consent, aged 18 years or more with primary
 moderate eumycetoma (size 2-10 cm) caused by Polymerase Chain Reaction (PCR) confirmed
 Madurella mycetomatis. Females in the child bearing age will require stringent contraception.
 The main exclusion criteria are eumycetoma > 10 cm, previous treatment, significant
 concomitant illness that preclude evaluation and treatments or conditions treated with drugs
 that are known to interact with the azoles.

 The study is expected to new safer and more efficacious eumycetoma treatment.
4.1. Inclusion criteria

 Subjects must meet all of the following inclusion criteria to be eligible for enrollment
 into the study:

 1. Subjects with eumycetoma caused by Madurella mycetomatis confirmed by PCR.

 2. Eumycetoma lesion ≥ 2 cm and <10 cm in diameter

 3. Single eumycetoma lesion present on the foot or lower limb

 4. Age ≥18 years

 5. Able to comply with protocol procedures and available for follow-up

 6. Written informed consent from the subject

 7. Female specific inclusion criteria

 -  Negative pregnancy test

 -  If female of child bearing potential, using adequate contraception for the period
 of the trial to 2 months after completing study treatment 4.2. Exclusion criteria

 The presence of any of the following will exclude a subject from study enrolment:

 1. Previous surgical or medical treatment for eumycetoma which includes with any previous
 antifungal treatment

 2. Presence of loco-regional lymphatic extension, osteomyelitis, other bone involvement
 based on radiology or any pre- or co-existing condition that would preclude evaluation
 of the eumycetoma.

 3. Pregnancy or lactation at screening, intent to become pregnant

 4. Concomitant or severe diseases that may compromise the subject follow-up or evaluation
 (psychiatric condition, chronic hepatitis, neutropenia, or HIV/AIDS, diabetes
 mellitus, adrenocortical insufficiency for example)

 5. Contraindication to the use of itraconazole including congestive heart failure,
 ventricular dysfunction, ventricular arrhythmia, negative inotropic state. For a
 comprehensive list of contraindications and contraindicated concomitant medication
 refer to the package insert for itraconazole (Sporanox®)

 6. Contraindication to the use of fosravuconazole

 7. Pre-existing liver disease, transaminase levels >2 x the laboratory's Upper Limit of
 Normal (ULN), or elevated levels of alkaline phosphatase or bilirubin

 8. Receiving or likely to require drugs that are either a substrate for CYP3A4 and/or
 metabolized by CYP3A4 (cisapride, oral midazolam, nisoldipine, felodipine, pimozide,
 quinidine, dofetilide, triazolam, methadone, and levacetylmethadol [levomethadyl] are
 contraindicated)

 9. Corrected QT by Fridericia's formula (QTcF) >450 msec on any ECG known about or taken
 prior to entry

 10. Subjects with Familial Short QT syndrome or (corrected QT interval) QTc prolongation

 11. History of hypersensitivity to any azole antifungal drug.

 12. Participation in other clinical trials within a six-month period.