Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial
| Autor: | Manica Balasegaram, Neal Alexander, Anke E. Kip, Mohammed Hassan Sharaf Ali, Eltahir A G Khalil, Gerard J. Schoone, Simon Njenga, Sally Ellis, Susan Wells, Thomas P. C. Dorlo, Robert Kimutai, Monique Wasunna, Joseph Olobo, Asrat Hailu, Fabiana Alves, Raymond Omollo, Brima Musa, Nathalie Strub Wourgaft, Mohammed Yasein Elamin, G. Kirigi, Ahmed Eleojo Musa, Rashid Juma, Tansy Edwards |
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| Přispěvatelé: | Sub Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Physiology Parasite Load Body Mass Index law.invention Sudan Pharmacology Toxicology and Pharmaceutics(all) 0302 clinical medicine Randomized controlled trial law Zoonoses Medicine and Health Sciences Clinical endpoint Medicine Child Leishmaniasis Pharmaceutics lcsh:Public aspects of medicine Hematology Middle Aged Body Fluids Treatment Outcome Blood Infectious Diseases Physiological Parameters Research Design Leishmaniasis Visceral Drug Therapy Combination Female Public Health Anatomy Research Article Neglected Tropical Diseases medicine.drug Adult medicine.medical_specialty lcsh:Arctic medicine. Tropical medicine Adolescent Clinical Research Design Sodium stibogluconate lcsh:RC955-962 Phosphorylcholine 030106 microbiology 030231 tropical medicine Antiprotozoal Agents Research and Analysis Methods Young Adult Kala-Azar 03 medical and health sciences Drug Therapy Amphotericin B Internal medicine Parasitic Diseases Humans Pharmacokinetics Pharmacology Miltefosine Protozoan Infections business.industry Body Weight Environmental and Occupational Health Public Health Environmental and Occupational Health Biology and Life Sciences lcsh:RA1-1270 Tropical Diseases medicine.disease Kenya Surgery Clinical trial Regimen Toxicology and Pharmaceutics(all) Visceral leishmaniasis Antimony Sodium Gluconate Adverse Events business Leishmania donovani |
| Zdroj: | PLoS Neglected Tropical Diseases, Vol 10, Iss 9, p e0004880 (2016) PLoS Neglected Tropical Diseases, 10(9), 1. Public Library of Science PLoS Neglected Tropical Diseases |
| ISSN: | 1935-2735 1935-2727 0106-7443 |
| Popis: | Background 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. Methods 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. Results 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. Conclusion 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. Trial Registration The study was registered with ClinicalTrials.gov, number NCT01067443 Author Summary Visceral leishmaniasis, or kala-azar, is a parasitic disease which is fatal without treatment. A 17-day treatment of sodium stibogluconate (SSG) with paromomycin (PM) is the recommended treatment in eastern Africa, but requires painful injections, causes adverse events, and patients need to stay in the hospital during treatment. An affordable, safe and effective oral treatment would be preferable. Whilst research to identify entirely new drugs is underway, existing treatments are being optimized as a short-term solution. Combination regimens based on AmBisome and miltefosine have been shown to be safe and effective in treating Indian patients, but there are no published data from use of these drugs in combination regimens from Africa, where efficacy of treatments can be different from India. Three regimens were evaluated for treating VL in eastern Africa, using AmBisome in combination with SSG or miltefosine, or miltefosine alone. Once again, drugs which are effective in India were found to be less so in African patients, and none of the regimes tested showed sufficiently high definitive cure rates to evaluate in Phase III trials. The results also suggest miltefosine was under-dosed in children and so allometric dosing, which takes into account the differences in drug metabolism seen in children compared to adults, needs to be studied. |
| Databáze: | OpenAIRE |
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