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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified December 2011 by Drugs for Neglected Diseases.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Eisai Co., Ltd.
Information provided by (Responsible Party):
Drugs for Neglected Diseases
ClinicalTrials.gov Identifier:
NCT01489228
First received: November 24, 2011
Last updated: December 19, 2011
Last verified: December 2011
  Purpose

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.


Condition Intervention Phase
Chronic Chagas Disease, Indeterminate
Drug: E1224
Drug: Benznidazole
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Drugs for Neglected Diseases:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
    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


Secondary Outcome Measures:
  • Consistently negative serial qualitative PCR as a measure of sustained parasitological eradication [ Time Frame: 4, 6 and 12 months follow-up ] [ Designated as safety issue: No ]
  • Qualitative PCR as a measure of parasite eradication [ Time Frame: Day 8, 15, 36 , 65 and at 4, 6 and 12 months follow-up ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
  • Incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation [ Time Frame: Up to 12 months follow-up ] [ Designated as safety issue: Yes ]
  • Early and late predictors of sustainable response to treatments [ Time Frame: Up to 12 months follow-up ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 230
Study Start Date: June 2011
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: High Dose E1224
High Dose (HD - 8weeks) Group
Drug: E1224
100 mg tablets
Other Name: E1224 (prodrug for active ingredient Ravuconazole)
Experimental: Low Dose E1224
Low Dose (LD - 8 weeks) Group
Drug: E1224
100 mg tablets
Other Name: E1224 (prodrug for active ingredient Ravuconazole)
Experimental: Short Dose E1224
Short Dose (SD - 4 weeks) Group
Drug: E1224
100 mg tablets
Other Name: 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 Name: Benznidazole (N-benzil-2-nitro-1-imidazolacetamida)

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

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01489228

Contacts
Contact: Fabiana P Alves, PhD +552122152941 falves@dndi.org

Locations
Bolivia
Plataforma de Atención Integral a los Pacientes con Enfermidad de Chagas Recruiting
Cochabamba, Bolivia
Contact: Faustino Torrico, PhD         
Contact: Cristina Alonso, MD         
Principal Investigator: Faustino Torrico, PhD         
Plataforma de Atención Integral a los Pacientes con Enfermidad de Chagas Recruiting
Tarija, Bolivia
Contact: Lourdes Ortiz, MSc         
Sub-Investigator: Lourdes Ortiz, MSc         
Sponsors and Collaborators
Drugs for Neglected Diseases
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.
  More Information

Additional Information:
No publications provided

Responsible Party: Drugs for Neglected Diseases
ClinicalTrials.gov Identifier: NCT01489228     History of Changes
Other Study ID Numbers: DNDi-CH-E1224-001
Study First Received: November 24, 2011
Last Updated: December 19, 2011
Health Authority: Bolivia: Ministry of Health
Bolivia: Ethics Committee
Spain: Ethics Committee

Keywords provided by Drugs for Neglected Diseases:
Chagas Disease

Additional relevant MeSH terms:
Chagas Disease
Trypanosomiasis
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Benzonidazole
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 22, 2014