Conference Material > Slide Presentation
Solomos A, Musa AM, Mbui J, Mohammed R, Olobo J, et al.
MSF Scientific Day International 2023. 2023 June 7; DOI:10.57740/81jj-tz57
Journal Article > ResearchFull Text
Am J Trop Med Hyg. 2007 August 1; Volume 77 (Issue 2); 275-282.
Alvar J, Bashaye S, Argaw D, Cruz I, Aparicio P, et al.
Am J Trop Med Hyg. 2007 August 1; Volume 77 (Issue 2); 275-282.
In May 2005, visceral leishmaniasis (VL) was recognized for the first time in Libo Kemkem, Ethiopia. In October 2005, a rapid assessment was conducted using data from 492 patients with VL treated in the district health center and a household survey of 584 residents of four villages. One subdistrict accounted for 71% of early cases, but the incidence and number of affected subdistricts increased progressively throughout 2004-2005. In household-based data, we identified 9 treated VL cases, 12 current untreated cases, and 19 deaths attributable to VL (cumulative incidence, 7%). Thirty percent of participants were leishmanin skin test positive (men, 34%; women, 26%; P = 0.06). VL was more common in men than women (9.7% versus 4.5%, P < 0.05), possibly reflecting male outdoor sleeping habits. Molecular typing in splenic aspirates showed L. infantum (six) and L. donovani (one). Local transmission resulted from multiple introductions, is now well established, and will be difficult to eradicate.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 2018 October 22; Volume 12 (Issue 10); e0006830.; DOI:10.1371/journal.pntd.0006830
Goyal V, Mahajan R, Pandey K, Singh SN, Singh RS, et al.
PLoS Negl Trop Dis. 2018 October 22; Volume 12 (Issue 10); e0006830.; DOI:10.1371/journal.pntd.0006830
BACKGROUND
In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions.
METHODS
This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891.
RESULTS
Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related.
CONCLUSION
All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India.
In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions.
METHODS
This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891.
RESULTS
Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related.
CONCLUSION
All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 2018 November 8; Volume 12 (Issue 11); DOI:10.1371/journal.pntd.0006778
Coulborn RM, Gebrehiwot TG, Schneider M, Gerstl S, Adera C, et al.
PLoS Negl Trop Dis. 2018 November 8; Volume 12 (Issue 11); DOI:10.1371/journal.pntd.0006778
Ethiopia bears a high burden of visceral leishmaniasis (VL). Early access to VL diagnosis and care improves clinical prognosis and reduces transmission from infected humans; however, significant obstacles exist. The approximate 250,000 seasonal mobile workers (MW) employed annually in northwestern Ethiopia may be particularly disadvantaged and at risk of VL acquisition and death. Our study aimed to assess barriers, and recommend interventions to increase access, to VL diagnosis and care among MWs.
Journal Article > ReviewFull Text
Lancet Global Health. 2021 December 1; Volume 9 (Issue 12); e1763-e1769.; DOI:10.1016/S2214-109X(21)00392-2
Alvar J, den Boer ML, Dagne DA
Lancet Global Health. 2021 December 1; Volume 9 (Issue 12); e1763-e1769.; DOI:10.1016/S2214-109X(21)00392-2
East Africa is the world region most affected by visceral leishmaniasis, accounting for 45% of cases globally that were reported to WHO in 2018, with an annual incidence that is only slightly decreasing. Unlike southeast Asia, east Africa does not have a regional approach to achieving elimination of visceral leishmaniasis as a public health problem. The goal of the WHO 2021-30 Neglected Tropical Diseases road map is to reduce mortality caused by the disease to less than 1%. To achieve this goal in east Africa, it will be necessary to roll out diagnosis and treatment at the primary health-care level and implement evidence-based personal protection methods and measures to reduce human-vector contact. Investment and collaboration to develop the necessary tools are scarce. In this Health Policy paper, we propose a strategic framework for a coordinated regional approach in east Africa for the elimination of visceral leishmaniasis as a public health problem.
Conference Material > Abstract
Solomos A, Musa AM, Mbui J, Mohammed R, Olobo J, et al.
MSF Scientific Day International 2023. 2023 June 7; 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 > CommentaryFull Text
Expert Opin Emerg Drugs. 2009 August 27; Volume 14 (Issue 3); DOI:10.1517/14728210903153862
den Boer ML, Alvar J, Davidson RN, Ritmeijer KKD, Balasegaram M
Expert Opin Emerg Drugs. 2009 August 27; Volume 14 (Issue 3); DOI:10.1517/14728210903153862
BACKGROUND: Visceral leishmaniasis (VL) is one of the most neglected parasitic diseases causing large scale mortality and morbidity among the poorest of the poor in the Indian subcontinent and Africa. OBJECTIVE: This review aims to describe the potential and the (lack of) current impact of newly developed treatments on the control of VL. It describes how the problem of an empty research pipeline is addressed, and discusses the emerging threat of incurable HIV/VL coinfection. METHODS: The literature was searched for drugs used in VL. CONCLUSION: Research and development of VL drugs has received a financial boost but no new drugs are expected in the next 5 years. Only three new and highly effective treatments have been licensed in the past 10 years. These remain, however, largely inaccessible as VL control programs in the developing world are lacking. This is deserving of immediate and urgent attention, especially in the context of the rapidly expanding HIV/VL coinfection.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 2019 February 21; DOI:10.1371/journal.pntd.0007132.
Diro EGJ, Edwards T, Ritmeijer KKD, Fikre H, Abongomera C, et al.
PLoS Negl Trop Dis. 2019 February 21; DOI:10.1371/journal.pntd.0007132.
BACKGROUND:
The long-term treatment outcome of visceral leishmaniasis (VL) patients with HIV co-infection is complicated by a high rate of relapse, especially when the CD4 count is low. Although use of secondary prophylaxis is recommended, it is not routinely practiced and data on its effectiveness and safety are limited.
METHODS:
A prospective cohort study was conducted in Northwest Ethiopia from August 2014 to August 2017 (NCT02011958). HIV-VL patients were followed for up to 12 months. Patients with CD4 cell counts below 200/μL at the end of VL treatment received pentamidine prophylaxis starting one month after parasitological cure, while those with CD4 count ≥200 cells/μL were followed without secondary prophylaxis. Compliance, safety and relapse-free survival, using Kaplan-Meier analysis methods to account for variable time at risk, were summarised. Risk factors for relapse or death were analysed.
RESULTS:
Fifty-four HIV patients were followed. The probability of relapse-free survival at one year was 50% (95% confidence interval [CI]: 35-63%): 53% (30-71%) in 22 patients with CD4 ≥200 cells/μL without pentamidine prophylaxis and 46% (26-63%) in 29 with CD4 <200 cells/μL who started pentamidine. Three patients with CD4 <200 cells/μL did not start pentamidine. Amongst those with CD4 ≥200 cells/μL, VL relapse was an independent risk factor for subsequent relapse or death (adjusted rate ratio: 5.42, 95% CI: 1.1-25.8). Except for one case of renal failure which was considered possibly related to pentamidine, there were no drug-related safety concerns.
CONCLUSION:
The relapse-free survival rate for VL patients with HIV was low. Relapse-free survival of patients with CD4 count <200cells/μL given pentamidine secondary prophylaxis appeared to be comparable to patients with a CD4 count ≥200 cells/μL not given prophylaxis. Patients with relapsed VL are at higher risk for subsequent relapse and should be considered a priority for secondary prophylaxis, irrespective of their CD4 count.
The long-term treatment outcome of visceral leishmaniasis (VL) patients with HIV co-infection is complicated by a high rate of relapse, especially when the CD4 count is low. Although use of secondary prophylaxis is recommended, it is not routinely practiced and data on its effectiveness and safety are limited.
METHODS:
A prospective cohort study was conducted in Northwest Ethiopia from August 2014 to August 2017 (NCT02011958). HIV-VL patients were followed for up to 12 months. Patients with CD4 cell counts below 200/μL at the end of VL treatment received pentamidine prophylaxis starting one month after parasitological cure, while those with CD4 count ≥200 cells/μL were followed without secondary prophylaxis. Compliance, safety and relapse-free survival, using Kaplan-Meier analysis methods to account for variable time at risk, were summarised. Risk factors for relapse or death were analysed.
RESULTS:
Fifty-four HIV patients were followed. The probability of relapse-free survival at one year was 50% (95% confidence interval [CI]: 35-63%): 53% (30-71%) in 22 patients with CD4 ≥200 cells/μL without pentamidine prophylaxis and 46% (26-63%) in 29 with CD4 <200 cells/μL who started pentamidine. Three patients with CD4 <200 cells/μL did not start pentamidine. Amongst those with CD4 ≥200 cells/μL, VL relapse was an independent risk factor for subsequent relapse or death (adjusted rate ratio: 5.42, 95% CI: 1.1-25.8). Except for one case of renal failure which was considered possibly related to pentamidine, there were no drug-related safety concerns.
CONCLUSION:
The relapse-free survival rate for VL patients with HIV was low. Relapse-free survival of patients with CD4 count <200cells/μL given pentamidine secondary prophylaxis appeared to be comparable to patients with a CD4 count ≥200 cells/μL not given prophylaxis. Patients with relapsed VL are at higher risk for subsequent relapse and should be considered a priority for secondary prophylaxis, irrespective of their CD4 count.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 2019 January 17; Volume 13 (Issue 1); DOI:10.1371/journal.pntd.0006988
Diro EGJ, Blesson S, Edwards T, Koert R, Ritmeijer KKD, et al.
PLoS Negl Trop Dis. 2019 January 17; Volume 13 (Issue 1); DOI:10.1371/journal.pntd.0006988
BACKGROUND
Visceral leishmaniasis (VL) in human immunodeficiency virus (HIV) co-infected patients requires special case management. AmBisome monotherapy at 40 mg/kg is recommended by the World Health Organization. The objective of the study was to assess if a combination of a lower dose of AmBisome with miltefosine would show acceptable efficacy at the end of treatment.
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, non-comparative randomized trial of AmBisome (30 mg/kg) with miltefosine (100 mg/day for 28 days), and AmBisome monotherapy (40 mg/kg) was conducted in Ethiopian VL patients co-infected with HIV (NCT02011958). A sequential design was used with a triangular continuation region. The primary outcome was parasite clearance at day 29, after the first round of treatment. Patients with clinical improvement but without parasite clearance at day 29 received a second round of the allocated treatment. Efficacy was evaluated again at day 58, after completion of treatment.
Recruitment was stopped after inclusion of 19 and 39 patients in monotherapy and combination arms respectively, as per pre-specified stopping rules. At D29, intention-to-treat efficacy in the AmBisome arm was 70% (95% CI 45–87%) in the unadjusted analysis, and 50% (95% CI 27–73%) in the adjusted analysis, while in the combination arm, it was 81% (95% CI 67–90%) and 67% (95% CI 48–82%) respectively. At D58, the adjusted efficacy was 55% (95% CI 32–78%) in the monotherapy arm, and 88% (95% CI 79–98%) in the combination arm.
No major safety concerns related to the study medication were identified. Ten SAEs were observed within the treatment period, and 4 deaths unrelated to the study medication.
CONCLUSIONS/SIGNIFICANCE
The extended treatment strategy with the combination regimen showed the highest documented efficacy in HIV-VL patients; these results support a recommendation of this regimen as first-line treatment strategy for HIV-VL patients in eastern Africa.
TRIAL REGISTRATION NUMBER
www.clinicaltrials.gov NCT02011958
Visceral leishmaniasis (VL) in human immunodeficiency virus (HIV) co-infected patients requires special case management. AmBisome monotherapy at 40 mg/kg is recommended by the World Health Organization. The objective of the study was to assess if a combination of a lower dose of AmBisome with miltefosine would show acceptable efficacy at the end of treatment.
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, non-comparative randomized trial of AmBisome (30 mg/kg) with miltefosine (100 mg/day for 28 days), and AmBisome monotherapy (40 mg/kg) was conducted in Ethiopian VL patients co-infected with HIV (NCT02011958). A sequential design was used with a triangular continuation region. The primary outcome was parasite clearance at day 29, after the first round of treatment. Patients with clinical improvement but without parasite clearance at day 29 received a second round of the allocated treatment. Efficacy was evaluated again at day 58, after completion of treatment.
Recruitment was stopped after inclusion of 19 and 39 patients in monotherapy and combination arms respectively, as per pre-specified stopping rules. At D29, intention-to-treat efficacy in the AmBisome arm was 70% (95% CI 45–87%) in the unadjusted analysis, and 50% (95% CI 27–73%) in the adjusted analysis, while in the combination arm, it was 81% (95% CI 67–90%) and 67% (95% CI 48–82%) respectively. At D58, the adjusted efficacy was 55% (95% CI 32–78%) in the monotherapy arm, and 88% (95% CI 79–98%) in the combination arm.
No major safety concerns related to the study medication were identified. Ten SAEs were observed within the treatment period, and 4 deaths unrelated to the study medication.
CONCLUSIONS/SIGNIFICANCE
The extended treatment strategy with the combination regimen showed the highest documented efficacy in HIV-VL patients; these results support a recommendation of this regimen as first-line treatment strategy for HIV-VL patients in eastern Africa.
TRIAL REGISTRATION NUMBER
www.clinicaltrials.gov NCT02011958
Journal Article > ResearchFull Text
Clin Infect Dis. 2022 September 27; 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. 2022 September 27; 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.