title: Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial.
abstract: SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa.
  
  
  
  A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments.
  
  
  
  In sequential analyses with 49-51 patients per arm, initial cure was 85% (95% CI: 73-92) in all arms. At D210, definitive cure was 87% (95% CI: 77-97) for AmBisome + SSG, 77% (95% CI 64-90) for AmBisome + miltefosine and 72% (95% CI 60-85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults.
  
  
  
  No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated.
  
  
  
  The study was registered with ClinicalTrials.gov, number NCT01067443.
authors.affiliation: Drugs for Neglected Diseases initiative, Nairobi, Kenya.|Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
authors.forename: Monique
authors.initials: M
authors.lastname: Wasunna
authors.affiliation: Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
authors.forename: Simon
authors.initials: S
authors.lastname: Njenga
authors.affiliation: Drugs for Neglected Diseases initiative, Geneva, Switzerland.
authors.forename: Manica
authors.initials: M
authors.lastname: Balasegaram
authors.affiliation: MRC Tropical Epidemiology Group, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Neal
authors.initials: N
authors.lastname: Alexander
authors.affiliation: Drugs for Neglected Diseases initiative, Nairobi, Kenya.
authors.forename: Raymond
authors.initials: R
authors.lastname: Omollo
authors.affiliation: MRC Tropical Epidemiology Group, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Tansy
authors.initials: T
authors.lastname: Edwards
authors.affiliation: Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Thomas P C
authors.initials: TP
authors.lastname: Dorlo
authors.affiliation: Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
authors.forename: Brima
authors.initials: B
authors.lastname: Musa
authors.affiliation: Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
authors.forename: Mohammed Hassan Sharaf
authors.initials: MH
authors.lastname: Ali
authors.affiliation: Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
authors.forename: Mohammed Yasein
authors.initials: MY
authors.lastname: Elamin
authors.affiliation: Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
authors.forename: George
authors.initials: G
authors.lastname: Kirigi
authors.affiliation: Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
authors.forename: Rashid
authors.initials: R
authors.lastname: Juma
authors.affiliation: Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.|Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Anke E
authors.initials: AE
authors.lastname: Kip
authors.affiliation: KIT Biomedical Research, Amsterdam, the Netherlands.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Schoone
authors.affiliation: College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Asrat
authors.initials: A
authors.lastname: Hailu
authors.affiliation: Department of Medical Microbiology, Leishmaniasis Unit, College of Health Sciences, Makerere University, Kampala, Uganda.
authors.forename: Joseph
authors.initials: J
authors.lastname: Olobo
authors.affiliation: Drugs for Neglected Diseases initiative, Geneva, Switzerland.
authors.forename: Sally
authors.initials: S
authors.lastname: Ellis
authors.affiliation: Drugs for Neglected Diseases initiative, Nairobi, Kenya.|Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
authors.forename: Robert
authors.initials: R
authors.lastname: Kimutai
authors.affiliation: Drugs for Neglected Diseases initiative, Geneva, Switzerland.
authors.forename: Susan
authors.initials: S
authors.lastname: Wells
authors.affiliation: Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
authors.forename: Eltahir Awad Gasim
authors.initials: EA
authors.lastname: Khalil
authors.affiliation: Drugs for Neglected Diseases initiative, Geneva, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strub Wourgaft
authors.affiliation: Drugs for Neglected Diseases initiative, Geneva, Switzerland.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Alves
authors.affiliation: Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Musa
mesh_terms: D000293:Adolescent; D000328:Adult; D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects; D000967:Antimony Sodium Gluconate / Q000008:administration & dosage* / Q000009:adverse effects; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002648:Child; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007630:Kenya; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D059208:Parasite Load; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013397:Sudan; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000981:Antiprotozoal Agents; C068538:liposomal amphotericin B; D010767:Phosphorylcholine; C039128:miltefosine; D000666:Amphotericin B; D000967:Antimony Sodium Gluconate