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Study to Evaluate Fexinidazole Dosing Regimens for the Treatment of Adult Patients With Chagas Disease

Primary Purpose

Chagas Disease, Trypanosomiasis, South American, South American Trypanosomiasis

Status
Unknown status
Phase
Phase 2
Locations
Bolivia
Study Type
Interventional
Intervention
Fexinidazole
Placebo
Sponsored by
Drugs for Neglected Diseases
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chagas Disease focused on measuring Chagas Disease, Dosage forms, Regimens

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Confirmed diagnosis of T. cruzi infection by Serial qualitative PCR (three samples collected over a single day, at least one of which must be positive) AND Conventional serology (a minimum of two out of three positive tests must be positive [Conventional ELISA, Recombinant Elisa or IIF)
  • Women in reproductive age must have a negative serum pregnancy test at screening, must not be breastfeeding, and consistently use a highly effective contraceptive method during the entire trial.
  • Normal EKG (PR ≤200 msec, QRS ≤120 msec, and QTc ≥400msec and ≤450 msec interval durations) at screening

Exclusion Criteria:

  • Signs and/or symptoms of chronic cardiac and/or digestive form of CD (as per Study Manual of Operations)
  • History of cardiomyopathy, heart failure or ventricular arrhythmia
  • Any other acute or chronic health conditions that, in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the study drug (such as acute infections, history of HIV infection, diabetes, liver and renal disease requiring medical treatment)
  • Laboratory test values considered clinically significant or out of the allowable range at screening as follows:

    • Total WBC must be within the normal range, with an acceptable margin of +/- 5% (3,800 - 10,500 / mm3).
    • Platelets must be within the normal range up to 550,000 / mm3
    • Total bilirubin must be within the normal range Transaminases (ALT and AST) must be within the normal range, with an acceptable margin of 25% above the upper limit of normality (ULN), < 1.25 x ULN.
    • Creatinine must be within an acceptable margin of 10% above the ULN, <1.10 x ULN.
    • Alkaline phosphatase must be within the normal range up to Grade 1 CTCAE (< 2.5 x ULN)
    • GGT must be within the normal range up to 2x ULN.
    • Potassium, Magnesium, Calcium must be within the normal range
  • 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.
  • Patients with contra-indication (known hypersensitivity) to other nitroimidazoles, e.g. metronidazole.
  • Any concomitant use of antimicrobial or anti-parasitic agents.

Sites / Locations

  • Plataforma Atención Integral de Pacientes con Enfermedad de ChagasRecruiting
  • Plataforma de Atención Integral de Pacientes con Enfermedad de ChagasRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Fexinidazole, 1800 mg, 2 weeks

Fexinidazole, 1800 mg, 4 weeks

Fexinidazole, 1800 mg, 8 weeks

Fexinidazole, 1200 mg, 2 weeks

Fexinidazole, 1200 mg, 4 weeks

Fexinidazole, 1200 mg, 8 weeks

Placebo

Arm Description

1800mg (High Dose) 2 weeks (HD - 2 weeks) Group: Fexinidazole, 1800 mg QD for 2 weeks, followed by placebo to complete 8 weeks (total dose: 25,2 g)

1800mg (High Dose) 4 weeks (HD - 4 weeks) Group: Fexinidazole, 1800 mg QD for 4 weeks, followed by placebo to complete 8 weeks (total dose: 50,4 g)

1800mg (High Dose) 8 weeks (HD - 8 weeks) Group: Fexinidazole, 1800 mg QD, for 8 weeks (total dose: 100,8 g)

1200mg (Dose 2 weeks) 2 weeks (LD - 2 weeks) Group: Fexinidazole, 1200 mg QD for 2 weeks, followed by placebo to complete 8 weeks (total dose: 16,8 g)

1200mg (Low Dose) 4 weeks (LD - 4 weeks) Group: Fexinidazole, 1200 mg QD for 4 weeks, followed by placebo to complete 8 weeks (total dose: 33,6 g)

1200mg (Low Dose) 8 weeks (LD - 8 weeks) Group: Fexinidazole, 1200 mg QD for 8 weeks (total dose: 67,2 g)

Placebo (8 weeks) Group: Fexinidazole matched placebo tablets QD for 8 weeks.

Outcomes

Primary Outcome Measures

Parasitological cure rate (PCR)
Parasitological cure rate as determined by serial negative qualitative PCR results (3 negative PCR results, from 3 samples to be collected in the same day) at end of treatment (8 weeks) and sustained parasitological clearance until 6 months follow-up.
Adverse events
Incidence and severity of adverse events (clinical, laboratory and EKG)
Serious Adverse events
Incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation

Secondary Outcome Measures

Parasite Clearance (qualitative PCR)
Parasite clearance at weeks 2, 3, 4, 6, 10, and at 4 and 6 months follow-up as measured by qualitative PCR
Parasite load
Change in parasite load over time assessed at weeks 2, 3, 4, 6, 10, and at 4 and 6 months follow-up as measured by quantitative PCR
Serological response
Serological response (conventional and non-conventional serologies) (incidence of conversion to negative and changes in titers over time) assessed at week 10 and at 4 and 6 months follow-up.
Blood culture for parasite genotyping
Blood culture and in vitro drug and susceptibility testing of isolated parasite strains at 6 months.

Full Information

First Posted
August 20, 2014
Last Updated
July 14, 2015
Sponsor
Drugs for Neglected Diseases
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1. Study Identification

Unique Protocol Identification Number
NCT02498782
Brief Title
Study to Evaluate Fexinidazole Dosing Regimens for the Treatment of Adult Patients With Chagas Disease
Official Title
Phase 2, Randomized, Multicenter, Placebo-controlled, Safety and Efficacy Study to Evaluate Six Oral Fexinidazole Dosing Regimens for the Treatment of Adult Patients With Chronic Indeterminate Chagas Disease.
Study Type
Interventional

2. Study Status

Record Verification Date
July 2015
Overall Recruitment Status
Unknown status
Study Start Date
July 2014 (undefined)
Primary Completion Date
September 2015 (Anticipated)
Study Completion Date
February 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Drugs for Neglected Diseases

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The hypothesis is to evaluate if the treatment with Fexinidazole will lead to a better sustained clearance of the parasites at 6 months of follow-up when in comparison to placebo in patients with chronic indeterminate CD.
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 100 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 PAHO (2006) indicate 7.54 million infected people and 55,185 new cases per year. New safe and effective treatments for Chagas Disease are urgently needed. Current chemotherapy options for CD have significant limitations, including long treatment durations, and safety and tolerability concerns. For many years, inhibitors of the sterol biosynthesis pathway, such as posaconazole and ravuconazole, were considered as the most promising new drugs candidates for Chagas Disease. Following the recent results of CHAGAZASOL, an investigator-initiated trial conducted in Barcelona, where a high recrudescence rate was observed in the posaconazole treatment arms (80-90%, versus 5% in the benznidazole arm), there is increased concern on the future of the class. Nitroimidazoles are a well-known class of pharmacologically active compounds, among which several have shown good activity against trypanosomes. While concerns over mutagenicity and safety have mitigated their potential as drug candidates, several members of this family are widely used as antibiotics, indicating that it is possible to select compounds with acceptable activity/toxicity profile in this class. Fexinidazole had been in preclinical development as a broad-spectrum antiprotozoal drug by Hoechst in the 1970s-1980s, but its clinical development was not pursued at the time. The molecule was ''rediscovered'' and selected for development by the Drugs for Neglected Diseases initiative (DNDi) as a new drug candidate for sleeping sickness, following a systematic review and profiling of more than 700 nitroheterocyclic compounds (mostly nitroimidazoles) from diverse sources, which included assessments of antiparasitic activity and mutagenic potential. Fexinidazole underwent extensive regulatory toxicology studies, including safety pharmacology (respiratory, cardiovascular, and general behaviour) and 4 weeks of repeated dose toxicokinetics studies in rat and dogs. 90-day toxicology studies were performed by Hoechst, allowing validation of the 3 months dosing in rat to a dose of 800 mg/kg/day and dog up to 125 mg/kg/day. Overall, Fexinidazole was found to be well tolerated, with no specific toxicity or other concerns. During 2010-2011, DNDi carried out several Phase I clinical trials assessing the safety and pharmacokinetics of Fexinidazole in human volunteers given in single and multiple doses. A pivotal phase II/III clinical safety and efficacy study in sleeping sickness patients was started in 2012 and to-date shows encouraging safety and tolerability profile and exposure in patients. Fexinidazole has previously been described as effective and superior to benznidazole or nifurtimox in one acute murine infection model with the T. cruzi Brazil 32 strain, but the methodologies used to establish cure are no longer considered the most accurate. More recently, in vitro studies performed at Institute Pasteur Korea (IPK) showed that Fexinidazole parent and metabolites (M1 and M2) are more or less equipotent versus T. cruzi in vitro (Tulahuen strain). Fexinidazole Sulfone (M2) is potent against a panel of T. cruzi strains (not including Colombiana or VL-10) albeit at higher concentrations than Benznidazole (2 to 4-fold). Fexinidazole Sulfone requires 72 to 96 hrs exposure at concentrations at or above 100 mM (31 mg/ml) with the Y strain; Benznidazole exhibits the same kinetics but requires exposure at the lower concentration of 12.5 mM (3.3 mg/ml).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chagas Disease, Trypanosomiasis, South American, South American Trypanosomiasis, Disease, Chagas
Keywords
Chagas Disease, Dosage forms, Regimens

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
140 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Fexinidazole, 1800 mg, 2 weeks
Arm Type
Active Comparator
Arm Description
1800mg (High Dose) 2 weeks (HD - 2 weeks) Group: Fexinidazole, 1800 mg QD for 2 weeks, followed by placebo to complete 8 weeks (total dose: 25,2 g)
Arm Title
Fexinidazole, 1800 mg, 4 weeks
Arm Type
Active Comparator
Arm Description
1800mg (High Dose) 4 weeks (HD - 4 weeks) Group: Fexinidazole, 1800 mg QD for 4 weeks, followed by placebo to complete 8 weeks (total dose: 50,4 g)
Arm Title
Fexinidazole, 1800 mg, 8 weeks
Arm Type
Active Comparator
Arm Description
1800mg (High Dose) 8 weeks (HD - 8 weeks) Group: Fexinidazole, 1800 mg QD, for 8 weeks (total dose: 100,8 g)
Arm Title
Fexinidazole, 1200 mg, 2 weeks
Arm Type
Active Comparator
Arm Description
1200mg (Dose 2 weeks) 2 weeks (LD - 2 weeks) Group: Fexinidazole, 1200 mg QD for 2 weeks, followed by placebo to complete 8 weeks (total dose: 16,8 g)
Arm Title
Fexinidazole, 1200 mg, 4 weeks
Arm Type
Active Comparator
Arm Description
1200mg (Low Dose) 4 weeks (LD - 4 weeks) Group: Fexinidazole, 1200 mg QD for 4 weeks, followed by placebo to complete 8 weeks (total dose: 33,6 g)
Arm Title
Fexinidazole, 1200 mg, 8 weeks
Arm Type
Active Comparator
Arm Description
1200mg (Low Dose) 8 weeks (LD - 8 weeks) Group: Fexinidazole, 1200 mg QD for 8 weeks (total dose: 67,2 g)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo (8 weeks) Group: Fexinidazole matched placebo tablets QD for 8 weeks.
Intervention Type
Drug
Intervention Name(s)
Fexinidazole
Other Intervention Name(s)
1Himidazole,1methyl2[4methylthio)phenoxymethyl] 5nitroimidazole
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Parasitological cure rate (PCR)
Description
Parasitological cure rate as determined by serial negative qualitative PCR results (3 negative PCR results, from 3 samples to be collected in the same day) at end of treatment (8 weeks) and sustained parasitological clearance until 6 months follow-up.
Time Frame
8 weeks and sustained until 6 months
Title
Adverse events
Description
Incidence and severity of adverse events (clinical, laboratory and EKG)
Time Frame
7 months
Title
Serious Adverse events
Description
Incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation
Time Frame
7 months
Secondary Outcome Measure Information:
Title
Parasite Clearance (qualitative PCR)
Description
Parasite clearance at weeks 2, 3, 4, 6, 10, and at 4 and 6 months follow-up as measured by qualitative PCR
Time Frame
weeks 2, 3, 4, 6, 10, and at 4 and 6 months follow-up
Title
Parasite load
Description
Change in parasite load over time assessed at weeks 2, 3, 4, 6, 10, and at 4 and 6 months follow-up as measured by quantitative PCR
Time Frame
weeks 2, 3, 4, 6, 10 and 4 and 6 months
Title
Serological response
Description
Serological response (conventional and non-conventional serologies) (incidence of conversion to negative and changes in titers over time) assessed at week 10 and at 4 and 6 months follow-up.
Time Frame
week 10, 4 and 6 months
Title
Blood culture for parasite genotyping
Description
Blood culture and in vitro drug and susceptibility testing of isolated parasite strains at 6 months.
Time Frame
6 months
Other Pre-specified Outcome Measures:
Title
Plasma level concentrations
Description
Plasma level concentrations of Fexinidazole and its metabolites M1 (sulfoxide) and M2 (sulfone) will be determined at D0 (pre-dose), at randomly selected time after first day of treatment administration (day 1, post-dose), at steady-state phase (week 2-9), and at week 10
Time Frame
D0 (pre-dose), at randomly selected time at day 1, post-dose, at steady-state phase (week 2-9), and at week 10

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Confirmed diagnosis of T. cruzi infection by Serial qualitative PCR (three samples collected over a single day, at least one of which must be positive) AND Conventional serology (a minimum of two out of three positive tests must be positive [Conventional ELISA, Recombinant Elisa or IIF) Women in reproductive age must have a negative serum pregnancy test at screening, must not be breastfeeding, and consistently use a highly effective contraceptive method during the entire trial. Normal EKG (PR ≤200 msec, QRS ≤120 msec, and QTc ≥400msec and ≤450 msec interval durations) at screening Exclusion Criteria: Signs and/or symptoms of chronic cardiac and/or digestive form of CD (as per Study Manual of Operations) History of cardiomyopathy, heart failure or ventricular arrhythmia Any other acute or chronic health conditions that, in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the study drug (such as acute infections, history of HIV infection, diabetes, liver and renal disease requiring medical treatment) Laboratory test values considered clinically significant or out of the allowable range at screening as follows: Total WBC must be within the normal range, with an acceptable margin of +/- 5% (3,800 - 10,500 / mm3). Platelets must be within the normal range up to 550,000 / mm3 Total bilirubin must be within the normal range Transaminases (ALT and AST) must be within the normal range, with an acceptable margin of 25% above the upper limit of normality (ULN), < 1.25 x ULN. Creatinine must be within an acceptable margin of 10% above the ULN, <1.10 x ULN. Alkaline phosphatase must be within the normal range up to Grade 1 CTCAE (< 2.5 x ULN) GGT must be within the normal range up to 2x ULN. Potassium, Magnesium, Calcium must be within the normal range 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. Patients with contra-indication (known hypersensitivity) to other nitroimidazoles, e.g. metronidazole. Any concomitant use of antimicrobial or anti-parasitic agents.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Isabela Ribeiro, MD
Phone
+552125290400
Email
iribeiro@dndi.org
First Name & Middle Initial & Last Name or Official Title & Degree
Fabiana BS Rocha, MD
Phone
+552125290400
Ext
0416
Email
fbarreira@dndi.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Faustino Torrico, MD
Organizational Affiliation
Plataforma de Antención Integral de Pacientes con Enfermedad de Chagas, Cochabamba, Bolivia
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Joaquim Gascón, MD
Organizational Affiliation
Centro de Salud Internacional, Hospital Clínico de Barcelona
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lourdes O Daza, MD
Organizational Affiliation
Plataforma de Antención Integral de Pacientes con Enfermedad de Chagas, Tarija, Bolivia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Plataforma Atención Integral de Pacientes con Enfermedad de Chagas
City
Cochabamba
Country
Bolivia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Faustino Torrico, MD
Phone
59177411905
Email
foxtorrico@yahoo.com
First Name & Middle Initial & Last Name & Degree
Cristina Alonso, MD
Phone
59172211312
Email
calonso@dndi.org
First Name & Middle Initial & Last Name & Degree
Faustino Torrico, MD
Facility Name
Plataforma de Atención Integral de Pacientes con Enfermedad de Chagas
City
Tarija
Country
Bolivia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lourdes O Daza, MD
Phone
5916672252
Email
lourdesortizd@yahoo.es
First Name & Middle Initial & Last Name & Degree
Erika Ribeiro, Pharm D
Phone
59175969924
Email
ecorreia@dndi.org
First Name & Middle Initial & Last Name & Degree
Lourdes O Daza, MD

12. IPD Sharing Statement

Learn more about this trial

Study to Evaluate Fexinidazole Dosing Regimens for the Treatment of Adult Patients With Chagas Disease

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