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

Study Status: Completed
Recruit Status: Unknown status
Study Type: Interventional

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 Indetermin

Brief Summary: 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.

Detailed Summary:

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, som
Sponsor: Drugs for Neglected Diseases

Current Primary Outcome: 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) ]

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


Original Primary Outcome: To determine the parasitological cure by serial negative qualitative Polymerase Chain Reaction (PCR) results (3 negative PCR results from 3 samples to be collected over 7 days) [ Time Frame: Day 65 (end of treatment) ]

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


Current Secondary Outcome:

  • Consistently negative serial qualitative PCR as a measure of sustained parasitological eradication [ Time Frame: 4, 6 and 12 months follow-up ]
  • Qualitative PCR as a measure of parasite eradication [ Time Frame: Day 8, 15, 36 , 65 and at 4, 6 and 12 months follow-up ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
    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 ]
  • Incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation [ Time Frame: Up to 12 months follow-up ]
  • Early and late predictors of sustainable response to treatments [ Time Frame: Up to 12 months follow-up ]
  • 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 ]


Original Secondary Outcome:

  • To assess the sustained parasitological eradication as determined by consistently negative serial qualitative PCR [ Time Frame: 4, 6 and 12 months follow-up ]
  • To determine the parasite eradication as measured by qualitative PCR [ Time Frame: Day 8, 15, 36 , 65 and at 4, 6 and 12 months follow-up ]
  • To assess the change in parasite load over time as measured by quantitative PCR [ Time Frame: Day 8, 15, 36, 65 and at 4, 6 and 12 months follow-up ]
  • To measure the 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 ]
  • To assess the 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 ]
  • To determine the population pharmacokinetic parameters 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 ]
  • To measure the incidence and severity of adverse events (clinical and laboratory) [ Time Frame: Up to 12 months follow-up ]
  • To monitor the incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation [ Time Frame: Up to 12 months follow-up ]
  • To determine early and late predictors of sustainable response to treatments [ Time Frame: Up to 12 months follow-up ]
  • To correlate 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 ]


Information By: Drugs for Neglected Diseases

Dates:
Date Received: November 24, 2011
Date Started: June 2011
Date Completion: December 2013
Last Updated: December 19, 2011
Last Verified: December 2011