Chronic Chagas Disease, Indeterminate Clinical Trial
Official title:
Phase 2 Randomized, Multicenter, Placebo-controlled, Safety and Efficacy Study to Evaluate Three Oral E1224 Dosing Regimens and Benznidazole for the Treatment of Adult Patients With Chronic Indeterminate Chagas Disease
This study will assess the safety and efficacy of E1224, a pro-drug of ravuconazole, in individuals with chronic indeterminate Chagas disease recruited in research centres in Tarija and Cochabamba, Bolivia.
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.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment