Evaluation of Fosmidomycin and Piperaquine in the Treatment of Acute Falciparum Malaria

Study Overview
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Brief Summary
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The objective of this study is to explore the role of fosmidomycin and piperaquine as non-artemisinin-based combination therapy for acute uncomplicated Plasmodium falciparum when administered over three days. Together, fosmidomycin and piperaquine fulfil the WHO criteria for combination therapy by meeting the three key parameters of having different modes of action and different biochemical targets while exhibiting independent blood schizonticidal activity. Like the artemisinins, fosmidomycin is fast-acting, has an excellent safety record and is active against existing drug-resistant parasites. Piperaquine has a long half life protecting fosmidomycin as a much shorter lived molecule against selection of resistant parasites and will provide post-treatment prophylaxis.

Official Title
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A Phase IIa Proof of Concept Study to Explore the Efficacy, Tolerability and Safety of Fosmidomycin Sodium When Administered With Piperaquine Tetraphosphate to Adults and Older Children With Acute Uncomplicated Plasmodium Falciparum Malaria

Conditions
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Oral Treatment of Acute Uncomplicated Plasmodium Falciparum Malaria

Intervention / Treatment
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* Drug: Fosmidomycin-Piperaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects aged 1 to 60 years inclusive Body weight between 5kg and 90kg inclusive Acute manifestations of a mono-infection with Plasmodium falciparum as determined by either a rapid diagnostic test for adults or microscopically confirmed by an asexual parasitaemia of 1,000 to 150,000/uL and fever with an axillary temperature of > 37.5 degress C or oral/rectal/tympanic temperature of > 38.0 degrees C or history of fever during the previous 72 hours Compliance with contraceptive measures throughout the study period of 63 days in females of child bearing potential Exclusion Criteria: To be eligible for inclusion in the study, subjects must NOT meet any of the following criteria: Signs of severe/complicated malaria according to WHO criteria Pregnancy as excluded by negative serum human chorionic gonadotrophin (hCG) test Lactation Mixed Plasmodium infection Severe vomiting on three or more occasions in the previous 24 hours Severe diarrhoea on four or more occasions in the previous 24 hours Concomitant disease masking assessment of response including abnormal liver function tests with bilirubin > 40 µmol/L, aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) levels > x 2 upper limit of normal impaired renal function with creatinine level > x 2 upper limit of normal haemoglobin level < 7.5g/dl white cell count > 12000/µL History of cardiovascular disease including arrhythmia with QTc interval ≥ 450msec, respiratory disease including active tuberculosis, hepatic disease including jaundice, renal failure, malignancy, neurological disorders including convulsions and psychiatric disturbances History of immunological disease including Hepatitis A, B and C and HIV-AIDS Severe malnutrition History of hypersensitivity or adverse reactions to fosmidomycin, piperaquine, artesunate and mefloquine Treatment with antimalarial and antibacterial agents within the previous 28 days

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fosmidomycin-Piperaquine<br>Fosmidomycin sodium capsules 450 mg, dosage: 30mg/kg twice daily for 3 days Piperaquine phosphate tablets 320 mg, dosage: 16 mg/kg once a day for 3 days | Drug: Fosmidomycin-Piperaquine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Per protocol, PCR-corrected cure rate on Day 28 | Six-hourly asexual counts until negative on three successive occasions. Weekly smears on days 7, 14, 21 and 28 | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Per protocol, PCR-corrected cure rates on Day 7 and Day 63 | Weekly smears on days 35 +/- 3 days, 42 +/- 3 days and 63 +/- 3 days | 63 days | 
| Derived parasite reduction ratio at 48 hours | Six-hourly asexual counts until negative on three successive occasions | 2 days | 
| Parasite clearance time | Six-hourly asexual counts until negative on three successive occasions | 96 hours | 
| Fever clearance time | Six hourly temperature recordings until normal on three successisve occasions | 96 hours | 
| Proportion of subjects with gametocytes on Day 7 | Smear on Day 7 | 7 days | 
| Adverse event recording | Recording of vital signs and ECG monitoring Recording of incidence, severity, drug-relatedness and seriousness of AEs and laboratory abnormalites | 28 days |