Evaluation of Fosmidomycin and Piperaquine in the Treatment of Acute Falciparum Malaria (FOSPIP)

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

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.

Study Overview

• Status: Unknown
• Conditions: Oral Treatment of Acute Uncomplicated Plasmodium Falciparum Malaria
• Intervention / Treatment: Drug: Fosmidomycin-Piperaquine

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fosmidomycin-Piperaquine; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Jomaa Pharma GmbH
• Collaborators: Centre de Recherche Médicale de Lambaréné

Publications and helpful links

General Publications

• Mombo-Ngoma G, Remppis J, Sievers M, Zoleko Manego R, Endamne L, Kabwende L, Veletzky L, Nguyen TT, Groger M, Lotsch F, Mischlinger J, Flohr L, Kim J, Cattaneo C, Hutchinson D, Duparc S, Moehrle J, Velavan TP, Lell B, Ramharter M, Adegnika AA, Mordmuller B, Kremsner PG. Efficacy and Safety of Fosmidomycin-Piperaquine as Nonartemisinin-Based Combination Therapy for Uncomplicated Falciparum Malaria: A Single-Arm, Age De-escalation Proof-of-Concept Study in Gabon. Clin Infect Dis. 2018 Jun 1;66(12):1823-1830. doi: 10.1093/cid/cix1122.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): July 1, 2014
• Study Completion (Anticipated): December 1, 2015

Study Registration Dates

• First Submitted: July 22, 2014
• First Submitted That Met QC Criteria: July 23, 2014
• First Posted (Estimate): July 24, 2014

Study Record Updates

• Last Update Posted (Estimate): June 15, 2015
• Last Update Submitted That Met QC Criteria: June 12, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Piperaquine; Fosmidomycin
• Other Study ID Numbers: JP017