Conference Material > Abstract
Fahal AH, Ahmed ES, Bakhiet SM, Bakheet OE, Fahal LA, et al.
MSF Scientific Day International 2024. 16 May 2024; DOI:10.57740/jZnxUIaJi7
INTRODUCTION
Treatment options for the highly neglected fungal tropical disease eumycetoma are limited and poorly adapted to patients’ contexts, with surgery often required. The first-line treatment, itraconazole, thought to be 40% effective, must be taken twice daily for ≥12 months with food, making adherence difficult. An effective, affordable, context-appropriate treatment is urgently needed. The Drugs for Neglected Diseases Initiative (DNDi) repurposed the broad-spectrum antifungal agent fosravuconazole, developed by Eisai Ltd for onychomycosis. We aimed to compare two different doses of weekly fosravuconazole with standard-of-care daily itraconazole in patients with eumycetoma.
METHODS
This phase 2, randomised, double-blind, active-controlled, superiority trial was done at the Mycetoma Research Centre, Soba University Hospital, Sudan. Patients aged ≥15 years with a small-to-medium lesion (≥2 to <16 cm) caused by M mycetomatis requiring surgery were randomly assigned (1:1:1) to receive either 300 mg fosravuconazole weekly (group 1), 200 mg fosravuconazole weekly (group 2), or 400 mg itraconazole daily (group 3), for 12 months, together with surgery at 6 months in all groups. The primary efficacy endpoint, assessed in all patients receiving at least one dose of study drug (modified intention to treat), was complete cure at 12 months (absence of eumycetoma mass and sinuses and discharge with normal imaging; or a negative fungal culture if mass present). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03086226).
RESULTS
Between 9 May, 2017, and 10 June, 2021, 104 patients were randomised (34 to group 1, 34 to group 2, and 36 to group 3).Median age was 29.0 (IQR22.0–33.0), 23.0 (20.0–29.0) and 24.5 (19.5–33.0) years for Groups 1, 2, and 3 respectively. Complete cure rates at end of treatment were 50.0% (95% CI 32.4–67.6), 64.7% (46.5–80.3), and 75.0% (57.8–87.9) with Groups 1, 2 and 3, respectively, showing no superiority of fosravuconazole over the standard-of-care (p=0.030 for Group 2 vs Group 3; and p=0.347 for Group 1 vs Group 3; with significance level set at 0.022). Treatment-emergent adverse drug reactions were reported in one (3%) of 34 patients in group 2 (nausea or vomiting) and three (8%) of 36 patients in group 3 (cortisol decreased, QT prolonged).
CONCLUSION
Although not superior, fosravuconazole 200 mg seemed to have similar efficacy to itraconazole, coupled with advantages such as a weekly, not daily, administration, no food effect, and low risk for drug-drug interactions. An early access programme is under review by authorities in Sudan and a regulatory dossier and global access plan are under preparation.
Treatment options for the highly neglected fungal tropical disease eumycetoma are limited and poorly adapted to patients’ contexts, with surgery often required. The first-line treatment, itraconazole, thought to be 40% effective, must be taken twice daily for ≥12 months with food, making adherence difficult. An effective, affordable, context-appropriate treatment is urgently needed. The Drugs for Neglected Diseases Initiative (DNDi) repurposed the broad-spectrum antifungal agent fosravuconazole, developed by Eisai Ltd for onychomycosis. We aimed to compare two different doses of weekly fosravuconazole with standard-of-care daily itraconazole in patients with eumycetoma.
METHODS
This phase 2, randomised, double-blind, active-controlled, superiority trial was done at the Mycetoma Research Centre, Soba University Hospital, Sudan. Patients aged ≥15 years with a small-to-medium lesion (≥2 to <16 cm) caused by M mycetomatis requiring surgery were randomly assigned (1:1:1) to receive either 300 mg fosravuconazole weekly (group 1), 200 mg fosravuconazole weekly (group 2), or 400 mg itraconazole daily (group 3), for 12 months, together with surgery at 6 months in all groups. The primary efficacy endpoint, assessed in all patients receiving at least one dose of study drug (modified intention to treat), was complete cure at 12 months (absence of eumycetoma mass and sinuses and discharge with normal imaging; or a negative fungal culture if mass present). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03086226).
RESULTS
Between 9 May, 2017, and 10 June, 2021, 104 patients were randomised (34 to group 1, 34 to group 2, and 36 to group 3).Median age was 29.0 (IQR22.0–33.0), 23.0 (20.0–29.0) and 24.5 (19.5–33.0) years for Groups 1, 2, and 3 respectively. Complete cure rates at end of treatment were 50.0% (95% CI 32.4–67.6), 64.7% (46.5–80.3), and 75.0% (57.8–87.9) with Groups 1, 2 and 3, respectively, showing no superiority of fosravuconazole over the standard-of-care (p=0.030 for Group 2 vs Group 3; and p=0.347 for Group 1 vs Group 3; with significance level set at 0.022). Treatment-emergent adverse drug reactions were reported in one (3%) of 34 patients in group 2 (nausea or vomiting) and three (8%) of 36 patients in group 3 (cortisol decreased, QT prolonged).
CONCLUSION
Although not superior, fosravuconazole 200 mg seemed to have similar efficacy to itraconazole, coupled with advantages such as a weekly, not daily, administration, no food effect, and low risk for drug-drug interactions. An early access programme is under review by authorities in Sudan and a regulatory dossier and global access plan are under preparation.
Conference Material > Slide Presentation
Fahal AH, Ahmed ES, Bakhiet SM, Bakheet OE, Fahal LA, et al.
MSF Scientific Day International 2024. 16 May 2024; DOI:10.57740/YDzkQTI
Conference Material > Slide Presentation
Solomos A, Musa AM, Mbui J, Mohammed R, Olobo J, et al.
MSF Scientific Day International 2023. 7 June 2023; DOI:10.57740/81jj-tz57
Conference Material > Abstract
Solomos A, Musa AM, Mbui J, Mohammed R, Olobo J, et al.
MSF Scientific Day International 2023. 7 June 2023; DOI:10.57740/y4z2-pq54
INTRODUCTION
The parasitic disease visceral leishmaniasis (VL) is most commonly caused by Leishmania donovani in eastern Africa, currently the region with highest burden worldwide. Current treatment for VL comprises the combination of sodium stibogluconate and paromomycin, SSG/PM; this is toxic, painful, and requires hospitalisation and daily injections. Treatments are urgently needed that are safe, effective, and appropriate for use in remote areas.
METHODS
We conducted a phase III open-label randomised non-inferiority trial in Ethiopia, Kenya, Sudan, and Uganda. The trial used a parallel-arm design with two arms, comparing the combination regimen of 20 mg/kg/day paromomycin and allometric miltefosine (MF) for 14 days with the current 17-day standard of care, 20 mg/kg/day SSG and 15 mg/kg/day PM. We enrolled adults and children aged 4-50 years with primary VL, without HIV or severe concomitant disease co-infection. The primary endpoint was definitive cure at 6 months’ follow-up.
ETHICS
This study was approved by the MSF Ethics Review Board and by ethics committees at the Institute of Endemic Diseases, Khartoum, Sudan; Kenya Medical Research Institute, Nairobi, Kenya; Makerere University, Uganda; and the University of Gondar, Ethiopia. Clinicaltrials.gov registry number, NCT03129646.
RESULTS
439 predominantly male (80%) patients aged 4 to 50 years were recruited over a period of 29 months. A similar proportion of patients in the PM/MF and the SSG/PM arms achieved definitive cure at 6-month follow-up in primary efficacy analysis using modified intention-to-treat; mITT; 91.2% cure for PM/MF (97.5% confidence interval, CI, 85-98.6) and 91.8% for SSG/PM (97.5% CI, 85.6-99.2). Non-inferiority was not demonstrated in the mITT population, with the upper limit of the 97.5% CI, 7.4%, slightly exceeding the non-inferiority margin of 7%. However, the per protocol analysis did show non-inferiority, with 92% (97.5% CI, 85-98.5) cure in the PM/MF arm, as compared to 91.7% (97.5% CI, 84.7-98.2) in the SSG/PM arm. Most adverse drug reactions (ADR’s) were mild to moderate. The most common expected ADR’s were MF-related vomiting, and PM-related injection site pain and hypoacusis. ADR’s suggesting SSG-related cardiac toxicity were reported in 6.5% (11/170) of patients in the SSG/PM arm. Eighteen serious adverse events were reported in 13 patients, four of which were considered related to study drugs. Fatality rate in the trial was 0.9% (4/439), with one death judged due to SSG-related cardiotoxicity.
CONCLUSION
The results of this study demonstrate that the 14-day PM/MF regimen achieved a clinically meaningful rate of cure with very similar efficacy to the standard of care, SSG/PM. It was generally well tolerated, with ADR’s as expected, based on the known safety profiles of study drugs. The PM/MF regimen has one fewer painful injection per day, a 3-day shorter treatment duration, and with no risk of SSG-associated life threating cardiotoxicity, as compared to SSG/PM. This regimen may therefore provide a more patient-friendly alternative for adults and children with VL in eastern Africa.
CONFLICTS OF INTEREST
None declared
The parasitic disease visceral leishmaniasis (VL) is most commonly caused by Leishmania donovani in eastern Africa, currently the region with highest burden worldwide. Current treatment for VL comprises the combination of sodium stibogluconate and paromomycin, SSG/PM; this is toxic, painful, and requires hospitalisation and daily injections. Treatments are urgently needed that are safe, effective, and appropriate for use in remote areas.
METHODS
We conducted a phase III open-label randomised non-inferiority trial in Ethiopia, Kenya, Sudan, and Uganda. The trial used a parallel-arm design with two arms, comparing the combination regimen of 20 mg/kg/day paromomycin and allometric miltefosine (MF) for 14 days with the current 17-day standard of care, 20 mg/kg/day SSG and 15 mg/kg/day PM. We enrolled adults and children aged 4-50 years with primary VL, without HIV or severe concomitant disease co-infection. The primary endpoint was definitive cure at 6 months’ follow-up.
ETHICS
This study was approved by the MSF Ethics Review Board and by ethics committees at the Institute of Endemic Diseases, Khartoum, Sudan; Kenya Medical Research Institute, Nairobi, Kenya; Makerere University, Uganda; and the University of Gondar, Ethiopia. Clinicaltrials.gov registry number, NCT03129646.
RESULTS
439 predominantly male (80%) patients aged 4 to 50 years were recruited over a period of 29 months. A similar proportion of patients in the PM/MF and the SSG/PM arms achieved definitive cure at 6-month follow-up in primary efficacy analysis using modified intention-to-treat; mITT; 91.2% cure for PM/MF (97.5% confidence interval, CI, 85-98.6) and 91.8% for SSG/PM (97.5% CI, 85.6-99.2). Non-inferiority was not demonstrated in the mITT population, with the upper limit of the 97.5% CI, 7.4%, slightly exceeding the non-inferiority margin of 7%. However, the per protocol analysis did show non-inferiority, with 92% (97.5% CI, 85-98.5) cure in the PM/MF arm, as compared to 91.7% (97.5% CI, 84.7-98.2) in the SSG/PM arm. Most adverse drug reactions (ADR’s) were mild to moderate. The most common expected ADR’s were MF-related vomiting, and PM-related injection site pain and hypoacusis. ADR’s suggesting SSG-related cardiac toxicity were reported in 6.5% (11/170) of patients in the SSG/PM arm. Eighteen serious adverse events were reported in 13 patients, four of which were considered related to study drugs. Fatality rate in the trial was 0.9% (4/439), with one death judged due to SSG-related cardiotoxicity.
CONCLUSION
The results of this study demonstrate that the 14-day PM/MF regimen achieved a clinically meaningful rate of cure with very similar efficacy to the standard of care, SSG/PM. It was generally well tolerated, with ADR’s as expected, based on the known safety profiles of study drugs. The PM/MF regimen has one fewer painful injection per day, a 3-day shorter treatment duration, and with no risk of SSG-associated life threating cardiotoxicity, as compared to SSG/PM. This regimen may therefore provide a more patient-friendly alternative for adults and children with VL in eastern Africa.
CONFLICTS OF INTEREST
None declared
Journal Article > ResearchFull Text
Clin Infect Dis. 27 September 2022; Online ahead of print; ciac643.; DOI:10.1093/cid/ciac643
Musa AM, Mbui J, Mohammed R, Olobo J, Ritmeijer KKD, et al.
Clin Infect Dis. 27 September 2022; Online ahead of print; ciac643.; DOI:10.1093/cid/ciac643
BACKGROUND
This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa.
METHODS
An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months.
RESULTS
Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], -6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, -0.3%; 97.5% CI, –7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug–related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (< 12 years) and adults.
CONCLUSIONS
PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa.
CLINICAL TRIALS REGISTRATION
NCT03129646.
This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa.
METHODS
An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months.
RESULTS
Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], -6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, -0.3%; 97.5% CI, –7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug–related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (< 12 years) and adults.
CONCLUSIONS
PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa.
CLINICAL TRIALS REGISTRATION
NCT03129646.