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

Drugs for Neglected Diseases

Status and phase: Unknown; Phase 2

Conditions: Chronic Chagas Disease, Indeterminate

Treatments: Drug: E1224; Drug: Placebo; Drug: Benznidazole

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT01489228

DNDi-CH-E1224-001

Details and patient eligibility

About

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.

Full 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.

Enrollment: 230 estimated patients

Sex: All

Ages: 18 to 50 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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230 participants in 5 patient groups, including a placebo group

High Dose E1224

Experimental group

Description:

High Dose (HD - 8weeks) Group

Treatment:

Drug: E1224

Low Dose E1224

Experimental group

Description:

Low Dose (LD - 8 weeks) Group

Treatment:

Drug: E1224

Short Dose E1224

Experimental group

Description:

Short Dose (SD - 4 weeks) Group

Treatment:

Drug: E1224

Placebo

Placebo Comparator group

Description:

Placebo (8 weeks) Group

Treatment:

Drug: Placebo

Benznidazol

Active Comparator group

Description:

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

Treatment:

Drug: Benznidazole