Proof-of-Concept Study of E1224 to Treat Adult Patients With Chagas Disease

• Serial negative qualitative Polymerase Chain Reaction (PCR) results (3 negative PCR results from 3 samples to be collected over 7 days) as a measure of parasitological cure at end of treatment [ Time Frame: Day 65 (end of treatment) ] [ Designated as safety issue: No ]
  To determine whether at least one of three dosing regimens of orally administered E1224 is more efficacious than placebo in individuals with chronic indeterminate CD, by determining the number of patients who convert from positive to negative in serial, qualitative PCR test results
  
  

• Consistently negative serial qualitative PCR as a measure of sustained parasitological eradication [ Time Frame: 4, 6 and 12 months follow-up ] [ Designated as safety issue: No ]
  
• Qualitative PCR as a measure of parasite eradication [ Time Frame: Day 8, 15, 36 , 65 and at 4, 6 and 12 months follow-up ] [ Designated as safety issue: No ]
  
• Quantitative PCR as a measure of change in parasite load over time [ Time Frame: Day 8, 15, 36, 65 and at 4, 6 and 12 months follow-up ] [ Designated as safety issue: No ]
  
• Incidence of serological conversion to negative and changes in titers over time as measured by conventional and non-conventional serologies [ Time Frame: Day 65 and at 4, 6 and 12 months after treatment ] [ Designated as safety issue: No ]
  
• Changes in the levels of biomarkers over time: brain natriuretic peptide, troponin T, selected prothrombotic factors, lytic antibodies, apolipoprotein A1 and multiplex serodiagnostic assay [ Time Frame: Day 36 , 65 and at 4, 6 and 12 months follow-up ] [ Designated as safety issue: No ]
  
• Area under the plasma concentration versus time curve (AUC), Peak Plasma Concentration (Cmax), Minimum Plasma Concentration (Cmin), Clearance, Volume of Distribution , and Plasma Terminal Half-Life (t1/2) of ravuconazole and benznidazole [ Time Frame: Day 0 (pre-dose), Day 1 (after 1st dose), Day 2, Day 3, steady-state phase (D8-D50), at the end of treatment (D65) and at the 4 months follow-up visit ] [ Designated as safety issue: No ]
  Samples for population pharmacokinetics parameters of ravuconazole and benznidazole will be collected at randomly selected time points on Days 1, 2 and 3.
  
  
• Incidence and severity of adverse events (clinical and laboratory) [ Time Frame: Up to 12 months follow-up ] [ Designated as safety issue: Yes ]
  
• Incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation [ Time Frame: Up to 12 months follow-up ] [ Designated as safety issue: Yes ]
  
• Early and late predictors of sustainable response to treatments [ Time Frame: Up to 12 months follow-up ] [ Designated as safety issue: No ]
  
• Correlation of pharmacokinetic parameters with parasitological response, changes in biomarkers and safety outcomes [ Time Frame: Day 8, 15, 36, 65, and at 4, 6 months and 12 months follow-up ] [ Designated as safety issue: Yes ]
  

Chagas disease (CD) ranks among the world's most neglected diseases. In Latin America, 21 countries are endemic for CD with an estimated 108 million people at risk of contracting the disease. Estimates from the 1980s indicated that some 16 million to 18 million individuals were infected. In the 1990s, after a series of multinational control initiatives, estimates of the number of infected people were revised to 9.8 million in 2001. The estimated burden of disease in terms of disability-adjusted life years (DALYs) declined from 2.7 million in 1990 to 586,000 in 2001. Recent estimates from Pan American Health Organization (PAHO, 2006) indicate 7.54 million infected people and 55,185 new cases per year.

The only two medicines available - benznidazole (BZN) and nifurtimox (NFX) - are known to cause serious toxicity with unsatisfactory cure rates, especially when used in adult chronic CD patients.

Novel antifungal triazole derivatives have arisen as alternative treatments for CD. They inhibit T. cruzi ergosterol biosynthesis, which is essential for parasite growth and survival, and have pharmacokinetic properties suitable for the treatment of this disseminated intracellular infection. Several triazole derivatives have been tested in animal models of CD, including D08701, posaconazole, ravuconazole (RAV), albaconazole, and TAK-187. In particular, RAV has previously been shown to have potent in vitro and in vivo activities, inducing parasitological cure in mice with acute infections, including those caused by benznidazole-resistant strains of T. cruzi. Suppressive activity was also seen in dog models.

E1224 is a water-soluble monolysine salt form of the RAV pro-drug. It is a broad-spectrum triazole antifungal with in vitro activity against most Candida and Aspergillus species, some non-Aspergillus species of filamentous fungi, Cryptococcus, dermatophytes, and fungi that cause the endemic mycoses.

RAV was evaluated extensively in animal models and in human trials including Phase 2 safety and efficacy trials in oropharyngeal and esophageal candidiasis and onychomycosis, and for prevention of invasive fungal infections in hematopoietic stem cell transplant recipients.

With the benign safety profile and the encouraging results of animal studies and favorable pharmacokinetics, E1224 is considered a priority candidate for clinical development for the treatment of Chagas' disease.

The general objective of this phase II trial is to determine whether each of three different dosing regimens of E1224 are efficacious and safe in eradicating T. cruzi parasitemia in individuals with the chronic indeterminate form of CD, in comparison to placebo.