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

Sponsor

Jomaa Pharma GmbH (Industry)

Overall Status

Unknown status

CT.gov ID

NCT01464125

Collaborator

Mahidol University (Other), Thammasat University (Other)

Enrollment

Location

Arm

Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: Fosmidomycin Drug: Azithromycin	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

43 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Nov 1, 2008

Actual Primary Completion Date :

Oct 1, 2009

Anticipated Study Completion Date :

Dec 1, 2011

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

day 28 cure rate of >95% [12 months]
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.
Safety and Tolerance [12 months]
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.
Day 7 cure rate of 100% [12 months]
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.

Secondary Outcome Measures

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 [12 months]
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.
PCR corrected cure rates [12 months]
to differentiate between reinfections and recrudescence

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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