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

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.

Study Overview

• Status: Unknown
• Conditions: Chronic Chagas Disease, Indeterminate
• Intervention / Treatment: Drug: Placebo; Drug: E1224; Drug: Benznidazole

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 230
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bolivia
  • Cochabamba, Bolivia
    • Recruiting
    • Plataforma de Atención Integral a los Pacientes con Enfermidad de Chagas
    • Contact: Faustino Torrico, PhD
    • Contact: Cristina Alonso, MD
    • Principal Investigator: Faustino Torrico, PhD
  • Tarija, Bolivia
    • Recruiting
    • Plataforma de Atención Integral a los Pacientes con Enfermidad de Chagas
    • Contact: Lourdes Ortiz, MSc
    • Sub-Investigator: Lourdes Ortiz, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Screening Criteria:

• Age >18 to < 50 years
• Weight > 40 kg
• Diagnosis of T. cruzi infection by conventional serology (a minimum of two out of three positive tests [enzyme linked immunosorbent assay (ELISA), indirect immunofluorescence (IIF), or hemagglutination inhibition (HAI)])
• Signed, written informed consent form
• No signs and/or symptoms of the chronic cardiac and/or digestive form of CD
• No acute or chronic health conditions that may interfere with the efficacy and/or safety evaluation of the study drug
• No formal contraindication to BZN and E1224
• No known history of hypersensitivity, allergic, or serious adverse reactions to the study drugs
• No history of CD treatment with BZN or NFX at any time in the past
• No history of systemic treatment with itraconazole, ketoconazole, posaconazole, isavuconazole, or allopurinol in the past

Inclusion Criteria:

• Confirmed diagnosis of T. cruzi infection by serial qualitative PCR AND Conventional serology
• Women in reproductive age must have a negative serum pregnancy test at screening, must not be breastfeeding, and consistently use and/or have partner consistently use an adequate contraceptive method
• Normal ECG at screening

Exclusion Criteria:

• Abnormal laboratory test values at screening for the following parameters: total White Blood Cells (WBC) count, platelet count, alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin, or creatinine; or gamma-glutamyl transferase (GGT)
• History of alcohol abuse or any other drug addiction (as specified in the Study Manual of Operations)
• Any condition that prevents the patient from taking oral medication
• Any concomitant use of antimicrobial or antiparasitic agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High Dose E1224; High Dose (HD - 8weeks) Group	Drug: E1224; 100 mg tablets; Other Names: E1224 (prodrug for active ingredient Ravuconazole)
Experimental: Low Dose E1224; Low Dose (LD - 8 weeks) Group	Drug: E1224; 100 mg tablets; Other Names: E1224 (prodrug for active ingredient Ravuconazole)
Experimental: Short Dose E1224; Short Dose (SD - 4 weeks) Group	Drug: E1224; 100 mg tablets; Other Names: E1224 (prodrug for active ingredient Ravuconazole)
Placebo Comparator: Placebo; Placebo (8 weeks) Group	Drug: Placebo; tablets
Active Comparator: Benznidazol; BZN (Laboratório do Estado de Pernambuco -LAFEPE, tablet 100mg), 5 mg/Kg/day PO divided in two daily doses, for 60 days	Drug: Benznidazole; 100mg tablets; Other Names: Benznidazole (N-benzil-2-nitro-1-imidazolacetamida)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	Day 65 (end of treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Consistently negative serial qualitative PCR as a measure of sustained parasitological eradication		4, 6 and 12 months follow-up
Qualitative PCR as a measure of parasite eradication		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		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		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		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	Samples for population pharmacokinetics parameters of ravuconazole and benznidazole will be collected at randomly selected time points on Days 1, 2 and 3.	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
Incidence and severity of adverse events (clinical and laboratory)		Up to 12 months follow-up
Incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation		Up to 12 months follow-up
Early and late predictors of sustainable response to treatments		Up to 12 months follow-up
Correlation of pharmacokinetic parameters with parasitological response, changes in biomarkers and safety outcomes		Day 8, 15, 36, 65, and at 4, 6 months and 12 months follow-up

Collaborators and Investigators

• Sponsor: Drugs for Neglected Diseases
• Collaborators: Eisai Co., Ltd.
• Investigators: Study Director: Isabela Ribeiro, MD, Drugs for Neglected Diseases initiative; Principal Investigator: Faustino Torrico, PhD, Universidad Mayor San Simón. Cochabamba, Bolivia.; Principal Investigator: Joaquim Gascón, PhD, CRESIB - Centre de Recerca en Salut Internacional de Barcelona, Spain.

Publications and helpful links

General Publications

• Parrado R, Ramirez JC, de la Barra A, Alonso-Vega C, Juiz N, Ortiz L, Illanes D, Torrico F, Gascon J, Alves F, Flevaud L, Garcia L, Schijman AG, Ribeiro I. Usefulness of Serial Blood Sampling and PCR Replicates for Treatment Monitoring of Patients with Chronic Chagas Disease. Antimicrob Agents Chemother. 2019 Jan 29;63(2):e01191-18. doi: 10.1128/AAC.01191-18. Print 2019 Feb.
• Torrico F, Gascon J, Ortiz L, Alonso-Vega C, Pinazo MJ, Schijman A, Almeida IC, Alves F, Strub-Wourgaft N, Ribeiro I; E1224 Study Group. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. Lancet Infect Dis. 2018 Apr;18(4):419-430. doi: 10.1016/S1473-3099(17)30538-8. Epub 2018 Jan 16.

Helpful Links

• Drugs for Neglected Diseases initiative

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Anticipated): August 1, 2012
• Study Completion (Anticipated): December 1, 2013

Study Registration Dates

• First Submitted: November 24, 2011
• First Submitted That Met QC Criteria: December 7, 2011
• First Posted (Estimate): December 9, 2011

Study Record Updates

• Last Update Posted (Estimate): December 21, 2011
• Last Update Submitted That Met QC Criteria: December 19, 2011
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Keywords: Chagas Disease
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Trypanosomiasis; Euglenozoa Infections; Chagas Disease; Physiological Effects of Drugs; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Antiprotozoal Agents; Antiparasitic Agents; Trypanocidal Agents; Benzonidazole
• Other Study ID Numbers: DNDi-CH-E1224-001