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

Malaria Clinical Trial

— JP011  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01464125
• Other study ID #: JP011
• Status: Active, not recruiting
• Phase: Phase 2
• First received: October 26, 2009
• Last updated: October 31, 2011
• Start date: November 2008
• Est. completion date: December 2011

Study information

• Verified date: October 2011
• Source: Jomaa Pharma GmbH
• Contact: n/a
• Is FDA regulated: No
• Health authority: Thailand: Ethical Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 43
• Est. completion date: December 2011
• Est. primary completion date: October 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 15 Years to 55 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum

Intervention

Drug:
• Fosmidomycin
Fosmidomycin sodium capsules 450 mg x 4 twelve-hourly for three days
• Azithromycin
Azithromycin capsules 250 mg x 3 twelve-hourly for three days

Locations

Country	Name	City	State
Thailand	Mahidol University	Bangkok

Sponsors (3)

Lead Sponsor	Collaborator
Jomaa Pharma GmbH	Mahidol University, Thammasat University

Country where clinical trial is conducted

Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	Yes
Primary	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	No
Secondary	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	No
Secondary	PCR corrected cure rates	to differentiate between reinfections and recrudescence	12 months	No