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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: 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

Brief Summary:

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 Summary:

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 ravuconaz
Sponsor: Drugs for Neglected Diseases

Current Primary Outcome: Proportion of patients with complete cure at the End-of-Treatment [ Time Frame: 12 months ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Proportion of patients with complete cure of the Mycetoma at the end of the study [ Time Frame: 15 months ]

  Complete cure of the mycetoma at the End Of Study (EOS; 15 months) visits Complete cure of mycetoma is defined as

  1. negative fungal culture from a surgical biopsy from the former mycetoma site AND
  2. clinical cure (no clinical evidence of mycetoma mass, sinus tract, or discharge) AND
  3. normal lesion site or only fibrosis on sonogram
• Proportion of patients with mycological eradication of Mycetoma [ Time Frame: 12 months ]
  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.
• Proportion of patients considered to have effective treatment at the End of Treament [ Time Frame: 12 months ]

  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.

• Proportion of patients considered to have effective treatment at the End of Study [ Time Frame: 12 months ]

  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.

• Propoprtion of patients with complete mycetoma cure by fungus genus at End of Treatment [ Time Frame: 12 months ]
  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
• Propoprtion of patients with complete mycetoma cure by fungus genus at End of Study [ Time Frame: 15 months ]
  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
• Immunological changes [ Time Frame: 15 months ]
  Immunological parameters indicating a switch from a Th2 to a Th1 response. This includes measurement of cytokines, immunoglobulins and cells
• Time to complete cure [ Time Frame: 15 months ]
  The time to onset of cure will be calculate for each subject
• Time to effective treatment [ Time Frame: 15 months ]
  The time to effective treatment will be calculate for each subject (combination of mycological eradication and clinical improvement in the mycetoma lesion).
• Time to failure [ Time Frame: 15 months ]
  The time to relapse will be calculate for each subject
• The proportion of subjects experiencing at least one Adverse Event [ Time Frame: 15 months ]
  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.
• The frequency of the Adverse Events and Serious Adverse Events that lead to treatment discontinuation. [ Time Frame: 15 months ]
  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.
• Severity of the Adverse Events and Serious Adverse Events that lead to treatment discontinuation. [ Time Frame: 15 months ]
  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.
• CMax [ Time Frame: 15 months ]
  Derived exposure parameters of ravuconazole and itraconazolecalculated from the final PK model using individual posterior estimates of the PK parameters and from dosing history.
• AUC at steady-state (AUCss) [ Tim
  
  

  Original Secondary Outcome: Same as current
  
  Information By: Drugs for Neglected Diseases
  

  Dates:
  Date Received: January 25, 2017
  Date Started: April 30, 2017
  Date Completion: March 31, 2020
  Last Updated: April 21, 2017
  Last Verified: April 2017