Fosmidomycin and Azithromycin for Acute Uncomplicated Plasmodium Falciparum Malaria (P. Malaria) in Adults (JP011)

Evaluation of Fosmidomycin and Azithromycin When Administered Concurrently to Adult Subjects With Acute Uncomplicated Plasmodium Falciparum Malaria

The aim of this study is to evaluate the role of azithromycin as a possible combination partner for fosmidomycin to protect it from its susceptibility to recrudescent infections when used as monotherapy for acute Plasmodium falciparum malaria while retaining its excellent safety profile.

Study Overview

• Status: Unknown
• Conditions: Malaria
• Intervention / Treatment: Drug: Fosmidomycin; Drug: Azithromycin

Detailed Description

The scientific rationale for the use of this combination is to inhibit the ability of the parasite to synthesise isoprenoids, as precursors of many essential compounds including sterols, carotenoids and ubiquinones. This is effected through blockade of the non-mevalonate pathway by fosmidomycin as a potent inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase coupled with targeting of protein biosynthesis by azithromycin through binding to the 50S ribosomal subunit. This mode of action contrasts with the ability of the human host to utilise the mevalonate pathway for isoprenoid synthesis and accounts for the safety profiles of both drugs through the mechanism of selective toxicity. Moreover it affords protection against cross resistance with existing chemotherapeutic agents.

The dose of fosmidomycin, equivalent to 30mg/kg twice daily for three days, selected for evaluation in this proof of concept study is derived from the highest dose that was administered in the Phase I safety tolerance studies. While the recommended dose of azithromycin for the treatment of bacterial infections is 250mg daily for three days, higher doses of up to 1500mg daily for three days have been evaluated for the treatment of malaria, in combination with artesunate or quinine.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand, 10400
    • Mahidol University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 55 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• male and female subjects aged 15 to 55 years
• body mass index ≥ 18.5kg/M2
• uncomplicated P falciparum malaria with acute manifestations
• asexual parasitaemia between 500uL and 100,000uL
• ability to tolerate oral therapy
• able to give informed signed consent

Exclusion Criteria:

• signs of severe malaria, according to WHO criteria
• body mass index ≤ 18.5 kg/M2
• pregnancy by history or by positive urine test
• lactation
• mixed plasmodial infection
• concomitant disease masking assessment of response, including diabetes, uncontrolled hypertension, heart failure, hepatic dysfunction (alanine-amino transferase > 150 U/L), renal impairment (creatinine > 125 umol/L or 3 mg/dl), haemoglobin < 8g/dl, white cell count > 12000/uL
• anti-malarial treatment within previous 28 days
• symptomatic AIDS

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fos-Azi; Open label single arm concurrent administration of fosmidomycin and azithromycin.	Drug: Fosmidomycin; Fosmidomycin sodium capsules 450 mg x 4 twelve-hourly for three days; Drug: Azithromycin; Azithromycin capsules 250 mg x 3 twelve-hourly for three days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
day 28 cure rate of >95%	Efficacy of fosmidomycin and azithromycin when co-administered to adults with acute uncomplicated P.falciparum malaria. Day 7 cure rate and Day 28 cure rates will be calculated from the following ratio: Number of subjects with clearance of asexual parasitaemia within seven days of commencement of treatment, without subsequent recrudescence within 28 days divided by total number of evaluable subjects.	12 months
Safety and Tolerance	To determine the safety and tolerance of fosmidomycin and azothromycin when co-administered orally over three days. Safety and tolerability will be evaluated by the incidence, intensity, seriousness and relationship of new adverse event(s), and clinically relevant laboratory changes. The drug will be considered as safe if there are no serious adverse events attributable to the study drug.	12 months
Day 7 cure rate of 100%	Efficacy of fosmidomycin and azithromycin when co-administered to adults with acute uncomplicated P.falciparum malaria. Day 7 cure rate and Day 28 cure rates will be calculated from the following ratio: Number of subjects with clearance of asexual parasitaemia within seven days of commencement of treatment, without subsequent recrudescence within 28 days divided by total number of evaluable subjects.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood samples at 0,1,2,3,4,6,8,12,14,18,24, 26,30,36,38,42,48,50,54,60,62,66,72,78,84,90,96,108,120,144.168.240 hours	pharmacokinetic profile. Full profiles of pharmacokinetic parameters including Cmax, Tmax, peak, trough, Vd, AUC, T1/2a, T1/2t, renal and total Cl will be derived.	12 months
PCR corrected cure rates	to differentiate between reinfections and recrudescence	12 months

Collaborators and Investigators

• Sponsor: Jomaa Pharma GmbH
• Collaborators: Mahidol University; Thammasat University
• Investigators: Principal Investigator: Srivicha Krudsood, Prof, Mahidol University

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): October 1, 2009
• Study Completion (Anticipated): December 1, 2011

Study Registration Dates

• First Submitted: October 26, 2009
• First Submitted That Met QC Criteria: October 31, 2011
• First Posted (Estimate): November 3, 2011

Study Record Updates

• Last Update Posted (Estimate): November 3, 2011
• Last Update Submitted That Met QC Criteria: October 31, 2011
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: Malaria; Plasmodium falciparum; acute uncomplicated
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin; Fosmidomycin
• Other Study ID Numbers: JP011