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.

Eligibility Criteria:
Inclusion Criteria

1. Participants with eumycetoma caused by M. mycetomatis confirmed by PCR.
2. Participants with eumycetoma requiring surgery.
3. Eumycetoma lesion ≥ 2 cm and \< 16 cm in diameter. Note: A lesion was defined as either one single lesion on one anatomical area or multiple lesions on one anatomical area provided that the total affected area remained within the given limits.
4. Age ≥ 15 years.
5. Able to comply with protocol procedures and available for follow-up.
6. Written informed consent from the participant. If the participant was \< 18 years old, there had to be a signed consent from a parent or legal guardian AND a written assent signed by the participant.
7. Female specific inclusion criteria:

   1. Negative pregnancy test.
   2. If women of childbearing potential (WOCBP), to use adequate contraception during the trial period until 2 months after completion of trial treatment.

Exclusion Criteria

1. Previous surgical or medical treatment for eumycetoma which included 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 could have precluded evaluation of the eumycetoma. Note: The presence of bone involvement would need a different treatment with a longer duration.
3. Pregnancy or lactation at screening, or intent to have become pregnant.
4. Concomitant or severe diseases that could have compromised the participant follow-up or evaluation (e.g., psychiatric condition, chronic hepatitis, neutropenia, human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), diabetes mellitus or adrenocortical insufficiency).
5. Severe malnutrition as defined by a body mass index (BMI) \< 16 kg/m2.
6. Contraindication to use itraconazole, including congestive heart failure, ventricular dysfunction, ventricular arrhythmia and negative inotropic state; Note: for a comprehensive list of contraindications and contraindicated concomitant medication refer to the package insert for itraconazole (Sporanox®);
7. Contraindication to the use of fosravuconazole;
8. Pre-existing liver disease, transaminase levels \> 2x the laboratory's upper limit of normal (ULN) or elevated levels of alkaline phosphatase (ALP) or bilirubin.
9. Was receiving or likely to have required drugs that were either a substrate for cytochrome P450 family 3 subfamily A member 4 (CYP3A4) and/or metabolised by CYP3A4 (cisapride, oral midazolam, nisoldipine, felodipine, pimozide, quinidine, dofetilide, triazolam, methodone and levacetylmethadol \[levomethadyl\] were contraindicated);
10. Fridericia's corrected QT interval (QTcF) \> 450 msec on any ECG known about or taken prior to trial entry.
11. Familial short QT syndrome or corrected QT interval (QTc) prolongation.
12. History of hypersensitivity to any azole antifungal drug.
13. Participation in other CTs within a 6-month period.