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

NCT03086226 | Completed Phase 2 DMC

• 1 other identifier: DNDi-FOSR-04-MYC
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 1

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.

Conditions

Mycetoma

Keywords

Mycetoma Fosravuconazole Itraconazole Surgery Sudan

Outcome Measures

Primary Outcomes (1)

• 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 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

  12 months

Secondary Outcomes (15)

• Proportion of patients with complete cure of the Mycetoma at the end of the study

  15 months

• Proportion of patients with mycological eradication of Mycetoma

  12 months

• Proportion of patients considered to have effective treatment at the End of Treament

  12 months

• Proportion of patients considered to have effective treatment at the End of Study

  12 months

• Propoprtion of patients with complete mycetoma cure by fungus genus at End of Treatment

  12 months

Study Arms (3)

Fosravuconazole 300 mg

EXPERIMENTAL

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

Fosravuconazole 200 mg weekly

EXPERIMENTAL

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

Itraconazole 400mg daily

ACTIVE COMPARATOR

Given throughout the study for 12 months as the comparator arm.

Drug: Itraconazole

Interventions

Fosravuconazole DRUG

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.

Also known as: E1224

Fosravuconazole 200 mg weekly; Fosravuconazole 300 mg

Itraconazole DRUG

This will be the active comparator

Also known as: Sporanox

Itraconazole 400mg daily

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants with eumycetoma caused by M. mycetomatis confirmed by PCR.
• Participants with eumycetoma requiring surgery.
• 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.
• Age ≥ 15 years.
• Able to comply with protocol procedures and available for follow-up.
• 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.
• Negative pregnancy test.
• If women of childbearing potential (WOCBP), to use adequate contraception during the trial period until 2 months after completion of trial treatment.

You may not qualify if:

• Previous surgical or medical treatment for eumycetoma which included 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 could have precluded evaluation of the eumycetoma. Note: The presence of bone involvement would need a different treatment with a longer duration.
• Pregnancy or lactation at screening, or intent to have become pregnant.
• 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).
• Severe malnutrition as defined by a body mass index (BMI) \< 16 kg/m2.
• 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®);
• Contraindication to the use of fosravuconazole;
• Pre-existing liver disease, transaminase levels \> 2x the laboratory's upper limit of normal (ULN) or elevated levels of alkaline phosphatase (ALP) or bilirubin.
• 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);
• Fridericia's corrected QT interval (QTcF) \> 450 msec on any ECG known about or taken prior to trial entry.
• Familial short QT syndrome or corrected QT interval (QTc) prolongation.
• History of hypersensitivity to any azole antifungal drug.
• Participation in other CTs within a 6-month period.

Sponsors & Collaborators

• Drugs for Neglected Diseases: lead

Study Sites (1)

Mycetoma Research Centre

Khartoum, Sudan

Location

Related Publications (2)

• Chu WY, Fahal AH, Ahmed ES, Bakhiet SM, Bakhiet OE, Fahal LA, Mohamed AA, Mohamedelamin ESW, Bahar MEN, Attalla HY, Siddig EE, Mhmoud NA, Musa AM, Oyieko P, Egondi T, Bruggemann RJ, Hata K, Strub-Wourgaft N, Alves F, Nyaoke BA, Zijlstra EE, Dorlo TPC. Pharmacokinetics and Pharmacodynamics of Fosravuconazole, Itraconazole, and Hydroxyitraconazole in Sudanese Patients With Eumycetoma. J Infect Dis. 2025 Sep 15;232(3):e518-e528. doi: 10.1093/infdis/jiaf279.

  PMID: 40433693 DERIVED

• Fahal AH, Ahmed ES, Bakhiet SM, Bakhiet OE, Fahal LA, Mohamed AA, Mohamedelamin ESW, Bahar MEN, Attalla HY, Siddig EE, Mhmoud NA, Musa AM, van de Sande WWJ, Scherrer B, Oyieko P, Egondi TW, Onyango KO, Hata K, Chu WY, Dorlo TPC, Bruggemann RJ, Nyaoke BA, Strub-Wourgaft N, Zijlstra EE. Two dose levels of once-weekly fosravuconazole versus daily itraconazole in combination with surgery in patients with eumycetoma in Sudan: a randomised, double-blind, phase 2, proof-of-concept superiority trial. Lancet Infect Dis. 2024 Nov;24(11):1254-1265. doi: 10.1016/S1473-3099(24)00404-3. Epub 2024 Aug 1.

  PMID: 39098321 DERIVED

MeSH Terms

Conditions

Mycetoma

Interventions

fosravuconazole L-lysine ethanolate; Itraconazole

Condition Hierarchy (Ancestors)

Nocardia Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Skin Diseases, Bacterial; Dermatomycoses; Mycoses; Skin Diseases, Infectious; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines

Study Officials

• Ahmed Fahal, Prof

  Mycetoma Research Centre, Soba University, Khartoum, Sudan

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 25, 2017
• First Posted: March 22, 2017
• Study Start: May 9, 2017
• Primary Completion: June 10, 2021
• Study Completion: March 7, 2022
• Last Updated: July 18, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Within 24 months of last subject last visit
• Access Criteria: Data Requestors will enter into an appropriate agreement or terms of use and will adhere to contractual obligations

Locations

SU (1)