Proof-of-Concept Study of E1224 to Treat Adult Patients With Chagas Disease
Primary Purpose
Chronic Chagas Disease, Indeterminate
Status
Unknown status
Phase
Phase 2
Locations
Bolivia
Study Type
Interventional
Intervention
E1224
Benznidazole
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Chagas Disease, Indeterminate focused on measuring Chagas Disease
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
Sites / Locations
- Plataforma de Atención Integral a los Pacientes con Enfermidad de ChagasRecruiting
- Plataforma de Atención Integral a los Pacientes con Enfermidad de ChagasRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Placebo Comparator
Active Comparator
Arm Label
High Dose E1224
Low Dose E1224
Short Dose E1224
Placebo
Benznidazol
Arm Description
High Dose (HD - 8weeks) Group
Low Dose (LD - 8 weeks) Group
Short Dose (SD - 4 weeks) Group
Placebo (8 weeks) Group
BZN (Laboratório do Estado de Pernambuco -LAFEPE, tablet 100mg), 5 mg/Kg/day PO divided in two daily doses, for 60 days
Outcomes
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
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
Qualitative PCR as a measure of parasite eradication
Quantitative PCR as a measure of change in parasite load over time
Incidence of serological conversion to negative and changes in titers over time as measured by conventional and non-conventional serologies
Changes in the levels of biomarkers over time: brain natriuretic peptide, troponin T, selected prothrombotic factors, lytic antibodies, apolipoprotein A1 and multiplex serodiagnostic assay
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.
Incidence and severity of adverse events (clinical and laboratory)
Incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation
Early and late predictors of sustainable response to treatments
Correlation of pharmacokinetic parameters with parasitological response, changes in biomarkers and safety outcomes
Full Information
NCT ID
NCT01489228
First Posted
November 24, 2011
Last Updated
December 19, 2011
Sponsor
Drugs for Neglected Diseases
Collaborators
Eisai Co., Ltd.
1. Study Identification
Unique Protocol Identification Number
NCT01489228
Brief Title
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
2. Study Status
Record Verification Date
December 2011
Overall Recruitment Status
Unknown status
Study Start Date
June 2011 (undefined)
Primary Completion Date
August 2012 (Anticipated)
Study Completion Date
December 2013 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Drugs for Neglected Diseases
Collaborators
Eisai Co., Ltd.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Chagas Disease, Indeterminate
Keywords
Chagas Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
230 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
High Dose E1224
Arm Type
Experimental
Arm Description
High Dose (HD - 8weeks) Group
Arm Title
Low Dose E1224
Arm Type
Experimental
Arm Description
Low Dose (LD - 8 weeks) Group
Arm Title
Short Dose E1224
Arm Type
Experimental
Arm Description
Short Dose (SD - 4 weeks) Group
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo (8 weeks) Group
Arm Title
Benznidazol
Arm Type
Active Comparator
Arm Description
BZN (Laboratório do Estado de Pernambuco -LAFEPE, tablet 100mg), 5 mg/Kg/day PO divided in two daily doses, for 60 days
Intervention Type
Drug
Intervention Name(s)
E1224
Other Intervention Name(s)
E1224 (prodrug for active ingredient Ravuconazole)
Intervention Description
100 mg tablets
Intervention Type
Drug
Intervention Name(s)
Benznidazole
Other Intervention Name(s)
Benznidazole (N-benzil-2-nitro-1-imidazolacetamida)
Intervention Description
100mg tablets
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
tablets
Primary Outcome Measure Information:
Title
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
Description
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
Time Frame
Day 65 (end of treatment)
Secondary Outcome Measure Information:
Title
Consistently negative serial qualitative PCR as a measure of sustained parasitological eradication
Time Frame
4, 6 and 12 months follow-up
Title
Qualitative PCR as a measure of parasite eradication
Time Frame
Day 8, 15, 36 , 65 and at 4, 6 and 12 months follow-up
Title
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
Title
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
Title
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
Title
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
Description
Samples for population pharmacokinetics parameters of ravuconazole and benznidazole will be collected at randomly selected time points on Days 1, 2 and 3.
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
Title
Incidence and severity of adverse events (clinical and laboratory)
Time Frame
Up to 12 months follow-up
Title
Incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation
Time Frame
Up to 12 months follow-up
Title
Early and late predictors of sustainable response to treatments
Time Frame
Up to 12 months follow-up
Title
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Fabiana P Alves, PhD
Phone
+552122152941
Email
falves@dndi.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Isabela Ribeiro, MD
Organizational Affiliation
Drugs for Neglected Diseases initiative
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Faustino Torrico, PhD
Organizational Affiliation
Universidad Mayor San Simón. Cochabamba, Bolivia.
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Joaquim Gascón, PhD
Organizational Affiliation
CRESIB - Centre de Recerca en Salut Internacional de Barcelona, Spain.
Official's Role
Principal Investigator
Facility Information:
Facility Name
Plataforma de Atención Integral a los Pacientes con Enfermidad de Chagas
City
Cochabamba
Country
Bolivia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Faustino Torrico, PhD
First Name & Middle Initial & Last Name & Degree
Cristina Alonso, MD
First Name & Middle Initial & Last Name & Degree
Faustino Torrico, PhD
Facility Name
Plataforma de Atención Integral a los Pacientes con Enfermidad de Chagas
City
Tarija
Country
Bolivia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lourdes Ortiz, MSc
First Name & Middle Initial & Last Name & Degree
Lourdes Ortiz, MSc
12. IPD Sharing Statement
Citations:
PubMed Identifier
30509941
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.
Results Reference
derived
PubMed Identifier
29352704
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.
Results Reference
derived
Links:
URL
http://www.dndi.org
Description
Drugs for Neglected Diseases initiative
Learn more about this trial
Proof-of-Concept Study of E1224 to Treat Adult Patients With Chagas Disease
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