Clinical trial NCT01489228: Proof-of-Concept Study of E1224 to Treat Adult Patients With Chagas Disease
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Chronic Chagas Disease, Indeterminate
Keywords: Chagas Disease
Lead sponsor: Drugs for Neglected Diseases
Sponsor class: OTHER
Collaborators: name: Eisai Co., Ltd.
First posted: 2011-12-09
Enrollment: 230
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

Eligibility 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

Primary outcomes:
measure: 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
timeFrame: Day 65 (end of treatment)
Secondary outcomes:
measure: Consistently negative serial qualitative PCR as a measure of sustained parasitological eradication
timeFrame: 4, 6 and 12 months follow-up
measure: Qualitative PCR as a measure of parasite eradication
timeFrame: Day 8, 15, 36 , 65 and at 4, 6 and 12 months follow-up
measure: Quantitative PCR as a measure of change in parasite load over time
timeFrame: Day 8, 15, 36, 65 and at 4, 6 and 12 months follow-up
measure: Incidence of serological conversion to negative and changes in titers over time as measured by conventional and non-conventional serologies
timeFrame: Day 65 and at 4, 6 and 12 months after treatment
measure: Changes in the levels of biomarkers over time: brain natriuretic peptide, troponin T, selected prothrombotic factors, lytic antibodies, apolipoprotein A1 and multiplex serodiagnostic assay
timeFrame: Day 36 , 65 and at 4, 6 and 12 months follow-up
measure: 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
timeFrame: 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
measure: Incidence and severity of adverse events (clinical and laboratory)
timeFrame: Up to 12 months follow-up
measure: Incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation
timeFrame: Up to 12 months follow-up
measure: Early and late predictors of sustainable response to treatments
timeFrame: Up to 12 months follow-up
measure: Correlation of pharmacokinetic parameters with parasitological response, changes in biomarkers and safety outcomes
timeFrame: Day 8, 15, 36, 65, and at 4, 6 months and 12 months follow-up
Other outcomes:
Locations:
city: Cochabamba
country: Bolivia
facility: Plataforma de Atención Integral a los Pacientes con Enfermidad de Chagas
city: Tarija
country: Bolivia
facility: Plataforma de Atención Integral a los Pacientes con Enfermidad de Chagas
Study officials:
affiliation: Drugs for Neglected Diseases initiative
name: Isabela Ribeiro, MD
role: STUDY_DIRECTOR
affiliation: Universidad Mayor San Simón. Cochabamba, Bolivia.
name: Faustino Torrico, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CRESIB - Centre de Recerca en Salut Internacional de Barcelona, Spain.
name: Joaquim Gascón, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.