Efficacy of Fosmidomycin-Clindamycin for Treating Malaria in Gabonese Children

Overview

There is a necessity for the development of new malaria drugs. Some antibiotics are also effective against malaria parasites. Fosmidomycin is an antibiotic that has been shown to be effective against malaria, although it cannot achieve a total cure in all patients. Previous small studies have shown that in combination with clindamycin, an commonly used antibiotic, it is highly effective and safe when given for three days, leading to a total cure in most patients. The current study will evaluate its efficacy in a larger population in Gabon, and compare its effect with the generally used drug, sulfadoxine-pyrimethamine.

Full Title of Study: “A Comparative Assessment of the Efficacy of Fosmidomycin-Clindamycin Versus Sulfadoxine-Pyrimethamine for the Treatment of Children With Uncomplicated Plasmodium Falciparum Malaria”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)

Detailed Description

Fosmidomycin-clindamycin (30 mg/kg and 10 mg/kg) given twice daily for three days is an effective and safe combination of antibiotics which demonstrated good activity against malaria parasite in previous phase II studies in African children. In this phase III trial, the efficacy and safety of the combination will be evaluated in African children with uncomplicated P. falciparum malaria. A single dose of sulfadoxine-pyrimethamine, the standard antimalarial in Gabon, is used as comparator.

Interventions

  • Drug: Fosmidomycin
    • 30 mg/kg
  • Drug: clindamycin
    • 10 mg/kg

Clinical Trial Outcome Measures

Primary Measures

  • Clinical and parasitological cure rate by day 28

Secondary Measures

  • Safety and tolerability of the two treatments during the entire study period
  • Parasite clearance time
  • Fever clearance time

Participating in This Clinical Trial

Inclusion Criteria

  • Uncomplicated P. falciparum malaria – P. falciparum asexual parasitaemia between 1,000/µL and 100,000/µL – Body weight between 10 – 65 kg – Ability to tolerate oral therapy – Informed consent, oral assent of the child, if possible – Residence in study area Exclusion Criteria:

  • Adequate anti-malarial treatment within the previous 7 days – Antibiotic treatment for the current infection – Previous participation in this clinical trial – Haemoglobin < 7 g/dl – Haematocrit < 23 % – Leucocyte count > 15,000 /µL – Mixed plasmodial infection – Severe malaria (as defined by WHO) – Any other severe underlying disease (cardiac, renal, hepatic diseases, malnutrition, known HIV infection) – Concomitant disease masking assessment of response – History of allergy or intolerance against trial medication

Gender Eligibility: All

Minimum Age: 3 Years

Maximum Age: 14 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Albert Schweitzer Hospital
  • Overall Official(s)
    • Saadou Issifou, MD, Principal Investigator, Albert Schweitzer Hospital

References

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Kuemmerle HP, Murakawa T, Soneoka K, Konishi T. Fosmidomycin: a new phosphonic acid antibiotic. Part I: Phase I tolerance studies. Int J Clin Pharmacol Ther Toxicol. 1985 Oct;23(10):515-20.

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Kuzuyama T, Shizimu T, Takashi S and Seto H. Fosmidomycin, a specific inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase in the nonmevalonate pathway of isoprenoid biosynthesis. Tetrahaedron Lett 1998;39:7913-6

Zeidler J, Schwender J, Müller C, et al. Inhibition of the non-mevalonate 1-deoxy-D-xylulose-5-phosphate pathway of plant isoprenoid biosynthesis by fosmidomycin. Z Naturforsch 1998;53:980-6

Lois LM, Campos N, Putra SR, Danielsen K, Rohmer M, Boronat A. Cloning and characterization of a gene from Escherichia coli encoding a transketolase-like enzyme that catalyzes the synthesis of D-1-deoxyxylulose 5-phosphate, a common precursor for isoprenoid, thiamin, and pyridoxol biosynthesis. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2105-10. doi: 10.1073/pnas.95.5.2105.

Takahashi S, Kuzuyama T, Watanabe H, Seto H. A 1-deoxy-D-xylulose 5-phosphate reductoisomerase catalyzing the formation of 2-C-methyl-D-erythritol 4-phosphate in an alternative nonmevalonate pathway for terpenoid biosynthesis. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9879-84. doi: 10.1073/pnas.95.17.9879.

Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, Turbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D, Beck E. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science. 1999 Sep 3;285(5433):1573-6. doi: 10.1126/science.285.5433.1573.

Kohler S, Delwiche CF, Denny PW, Tilney LG, Webster P, Wilson RJ, Palmer JD, Roos DS. A plastid of probable green algal origin in Apicomplexan parasites. Science. 1997 Mar 7;275(5305):1485-9. doi: 10.1126/science.275.5305.1485.

Fichera ME, Roos DS. A plastid organelle as a drug target in apicomplexan parasites. Nature. 1997 Nov 27;390(6658):407-9. doi: 10.1038/37132.

Borrmann S, Adegnika AA, Matsiegui PB, Issifou S, Schindler A, Mawili-Mboumba DP, Baranek T, Wiesner J, Jomaa H, Kremsner PG. Fosmidomycin-clindamycin for Plasmodium falciparum Infections in African children. J Infect Dis. 2004 Mar 1;189(5):901-8. doi: 10.1086/381785. Epub 2004 Feb 16.

Borrmann S, Issifou S, Esser G, Adegnika AA, Ramharter M, Matsiegui PB, Oyakhirome S, Mawili-Mboumba DP, Missinou MA, Kun JF, Jomaa H, Kremsner PG. Fosmidomycin-clindamycin for the treatment of Plasmodium falciparum malaria. J Infect Dis. 2004 Nov 1;190(9):1534-40. doi: 10.1086/424603. Epub 2004 Sep 21.

Shulman CE, Dorman EK, Cutts F, Kawuondo K, Bulmer JN, Peshu N, Marsh K. Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial. Lancet. 1999 Feb 20;353(9153):632-6. doi: 10.1016/s0140-6736(98)07318-8.

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Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg. 2000 Apr;94 Suppl 1:S1-90. No abstract available.

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