Proof-of-Concept Superiority Trial of Fosravuconazole Versus Itraconazole for Eumycetoma in Sudan

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized, Double Blind Phase II Proof-of-Concept Superiority Trial of Fosravuconazole 200 mg or 300 mg Weekly Dose Versus Itraconazole 400 mg Daily, All Three Arms in Combination With Surgery, in Patients With Eumycetoma in Sudan

Conditions
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Mycetoma

Intervention / Treatment
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* Drug: Fosravuconazole
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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4.1. Inclusion criteria Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study: Subjects with eumycetoma caused by Madurella mycetomatis confirmed by PCR. Eumycetoma lesion ≥ 2 cm and <10 cm in diameter Single eumycetoma lesion present on the foot or lower limb Age ≥18 years Able to comply with protocol procedures and available for follow-up Written informed consent from the subject 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: Previous surgical or medical treatment for eumycetoma which includes with any previous antifungal treatment 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. Pregnancy or lactation at screening, intent to become pregnant 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) 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®) Contraindication to the use of fosravuconazole Pre-existing liver disease, transaminase levels >2 x the laboratory's Upper Limit of Normal (ULN), or elevated levels of alkaline phosphatase or bilirubin 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) Corrected QT by Fridericia's formula (QTcF) >450 msec on any ECG known about or taken prior to entry Subjects with Familial Short QT syndrome or (corrected QT interval) QTc prolongation History of hypersensitivity to any azole antifungal drug. Participation in other clinical trials within a six-month period.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fosravuconazole 300 mg<br>Given throughout the study for 12 months as the experimental arm. Both experimental 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. | Drug: Fosravuconazole<br>* Fosravuconazole will be given in two arms either as 300mg or 200mg. The drop-the loser design adaptive clinical trial design will allow two stages of the trial separated by a data based decision. In the first stage a decision will be taken on which arm to drop either the Fosravuconazole 200 or the Fosravuconazole 300 arm. The best treatment will be compared against the standard of care, itraconazole. At the end the focus will be comparing the best treatment against standard of care.<br>* Other names: E1224;|
| Experimental: Fosravuconazole 200 mg weekly<br>Given throughout the study for 12 months as the experimental arm. Both experimental 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. | Drug: Fosravuconazole<br>* Fosravuconazole will be given in two arms either as 300mg or 200mg. The drop-the loser design adaptive clinical trial design will allow two stages of the trial separated by a data based decision. In the first stage a decision will be taken on which arm to drop either the Fosravuconazole 200 or the Fosravuconazole 300 arm. The best treatment will be compared against the standard of care, itraconazole. At the end the focus will be comparing the best treatment against standard of care.<br>* Other names: E1224;|
| Active Comparator: Itraconazole 400mg daily<br>Given throughout the study for 12 months as the comparator arm. | Drug: Itraconazole<br>* This will be the active comparator<br>* Other names: Sporanox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with complete cure at the End-of-Treatment | Complete cure at the End-of-Treatment (EOT; 52-week time point) in the Modified Intention to Treat (mITT) population. Complete cure of mycetoma is defined as negative fungal culture from a surgical biopsy from the former mycetoma site AND clinical cure (no clinical evidence of mycetoma mass, sinus tract, or discharge) AND normal lesion site or only fibrosis on sonogram | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with complete cure of the Mycetoma at the end of the study | Complete cure of the mycetoma at the End Of Study (EOS; 15 months) visits Complete cure of mycetoma is defined as negative fungal culture from a surgical biopsy from the former mycetoma site AND clinical cure (no clinical evidence of mycetoma mass, sinus tract, or discharge) AND normal lesion site or only fibrosis on sonogram | 15 months | 
| Proportion of patients with mycological eradication of Mycetoma | Mycological eradication of the etiologic fungal pathogen from the mycetoma biopsy at the EOT visit (52-week time point). Mycological eradication is defined as negative Mycetoma culture biopsy. | 12 months | 
| Proportion of patients considered to have effective treatment at the End of Treament | Effective treatment (combination of mycological eradication AND clinical improvement in the mycetoma lesion) at EOT (52-week time point) visit in the mITT and Clinically Evaluable (CE) Populations. Mycetoma clinical improvement is defined by reduction in mycetoma mass size. Mycological eradication is defined as negative Mycetoma culture biopsy. | 12 months | 
| Proportion of patients considered to have effective treatment at the End of Study | Effective treatment (combination of mycological eradication AND clinical improvement in the mycetoma lesion) at EOS (15 months) visit in the mITT and Clinically Evaluable (CE) Populations. Mycetoma clinical improvement is defined by reduction in mycetoma mass size. Mycological eradication is defined as negative Mycetoma culture biopsy. | 12 months | 
| Propoprtion of patients with complete mycetoma cure by fungus genus at End of Treatment | Complete cure, effective treatment, and overall improvement categorized by etiologic fungal genus and species at EOT (52-week time point) visits in the mITT and CE populations | 12 months | 
| Propoprtion of patients with complete mycetoma cure by fungus genus at End of Study | Complete cure, effective treatment, and overall improvement categorized by etiologic fungal genus and species at EOS (15 months) visits in the mITT and CE populations | 15 months | 
| Immunological changes | Immunological parameters indicating a switch from a Th2 to a Th1 response. This includes measurement of cytokines, immunoglobulins and cells | 15 months | 
| Time to complete cure | The time to onset of cure will be calculate for each subject | 15 months | 
| Time to effective treatment | The time to effective treatment will be calculate for each subject (combination of mycological eradication and clinical improvement in the mycetoma lesion). | 15 months | 
| Time to failure | The time to relapse will be calculate for each subject | 15 months | 
| The proportion of subjects experiencing at least one Adverse Event | The safety consists the description of each serious adverse event and adverse event (preferred term) per treatment group and classified by system organ. ECG and Laboratory abnormalities will be considered as Adverse Events. | 15 months | 
| The frequency of the Adverse Events and Serious Adverse Events that lead to treatment discontinuation. | The safety consists the description of each serious adverse event and adverse event (preferred term) per treatment group and classified by system organ. ECG and Laboratory abnormalities will be considered as Adverse Events. | 15 months | 
| Severity of the Adverse Events and Serious Adverse Events that lead to treatment discontinuation. | The safety consists the description of each serious adverse event and adverse event (preferred term) per treatment group and classified by system organ. ECG and Laboratory abnormalities will be considered as Adverse Events. | 15 months | 
| CMax | Derived exposure parameters of ravuconazole and itraconazolecalculated from the final PK model using individual posterior estimates of the PK parameters and from dosing history. | 15 months | 
| AUC at steady-state (AUCss) | Derived exposure parameters of ravuconazole and itraconazolecalculated from the final PK model using individual posterior estimates of the PK parameters and from dosing history. | 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mycetoma Fosravuconazole Itraconazole Surgery Sudan