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

NCT ID: NCT01489228

Last Updated: 2011-12-21

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE2

Total Enrollment

230 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-06-30

Study Completion Date

2013-12-31

Brief Summary

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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 Description

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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.

Conditions

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Chronic Chagas Disease, Indeterminate

Keywords

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Chagas Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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High Dose E1224

High Dose (HD - 8weeks) Group

Group Type EXPERIMENTAL

E1224

Intervention Type DRUG

100 mg tablets

Low Dose E1224

Low Dose (LD - 8 weeks) Group

Group Type EXPERIMENTAL

E1224

Intervention Type DRUG

100 mg tablets

Short Dose E1224

Short Dose (SD - 4 weeks) Group

Group Type EXPERIMENTAL

E1224

Intervention Type DRUG

100 mg tablets

Placebo

Placebo (8 weeks) Group

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

tablets

Benznidazol

BZN (Laboratório do Estado de Pernambuco -LAFEPE, tablet 100mg), 5 mg/Kg/day PO divided in two daily doses, for 60 days

Group Type ACTIVE_COMPARATOR

Benznidazole

Intervention Type DRUG

100mg tablets

Interventions

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E1224

100 mg tablets

Intervention Type DRUG

Benznidazole

100mg tablets

Intervention Type DRUG

Placebo

tablets

Intervention Type DRUG

Other Intervention Names

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E1224 (prodrug for active ingredient Ravuconazole) Benznidazole (N-benzil-2-nitro-1-imidazolacetamida)

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

50 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Eisai Co., Ltd.

INDUSTRY

Sponsor Role collaborator

Drugs for Neglected Diseases

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Isabela Ribeiro, MD

Role: STUDY_DIRECTOR

Drugs for Neglected Diseases initiative

Faustino Torrico, PhD

Role: PRINCIPAL_INVESTIGATOR

Universidad Mayor San Simón. Cochabamba, Bolivia.

Joaquim Gascón, PhD

Role: PRINCIPAL_INVESTIGATOR

CRESIB - Centre de Recerca en Salut Internacional de Barcelona, Spain.

Locations

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Plataforma de Atención Integral a los Pacientes con Enfermidad de Chagas

Cochabamba, Departamento de Cochabamba, Bolivia

Site Status RECRUITING

Plataforma de Atención Integral a los Pacientes con Enfermidad de Chagas

Tarija, Tarija Department, Bolivia

Site Status RECRUITING

Countries

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Bolivia

Central Contacts

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Fabiana P Alves, PhD

Role: CONTACT

Phone: +552122152941

Email: [email protected]

Facility Contacts

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Faustino Torrico, PhD

Role: primary

Cristina Alonso, MD

Role: backup

Lourdes Ortiz, MSc

Role: primary

References

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De Salazar PM, Sosa-Estani S, Salvador F, Sulleiro E, Sanchez-Montalva A, Ribeiro I, Molina I, Buckee CO. Human Trypanosoma cruzi chronic infection leads to individual level steady-state parasitemia: Implications for drug-trial optimization in Chagas disease. PLoS Negl Trop Dis. 2022 Nov 21;16(11):e0010828. doi: 10.1371/journal.pntd.0010828. eCollection 2022 Nov.

Reference Type DERIVED
PMID: 36409773 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30509941 (View on PubMed)

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.

Reference Type DERIVED
PMID: 29352704 (View on PubMed)

Related Links

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http://www.dndi.org

Drugs for Neglected Diseases initiative

Other Identifiers

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DNDi-CH-E1224-001

Identifier Type: -

Identifier Source: org_study_id