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BENDITA BEnznidazole New Doses Improved Treatment and Associations (BENDITA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03378661
Recruitment Status : Active, not recruiting
First Posted : December 20, 2017
Last Update Posted : December 20, 2017
Sponsor:
Information provided by (Responsible Party):
Drugs for Neglected Diseases

Brief Summary:

Recent scientific advances have provided further impetus to develop new therapeutic approaches for Chagas Disease (CD) using different doses and duration of BZN, as well as combinations directed at multiple therapeutic targets to improve treatment response and tolerability and reduce the potential for development of resistance.

This project focuses on the proof-of-concept evaluation of improved treatment regimens of BZN, with the assessment of new BZN-sparing regimens in monotherapy and in combination with E1224.


Condition or disease Intervention/treatment Phase
Chagas Disease Drug: Benznidazole Drug: E1224 Drug: E1224 Placebo Drug: Benznidazole Placebo Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double Dummy
Primary Purpose: Treatment
Official Title: Phase 2 Randomized, Multicenter, Safety and Efficacy Trial to Evaluate Different Oral Benznidazole Monotherapy and Benznidazole/E1224 Combination Regimens for the Treatment of Adult Patients With Chronic Indeterminate Chagas Disease
Actual Study Start Date : November 30, 2016
Estimated Primary Completion Date : January 28, 2018
Estimated Study Completion Date : July 27, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Chagas Disease

Arm Intervention/treatment
Experimental: BZN STD Regimen

Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 8 weeks.

Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.

Drug: Benznidazole
Benznidazole tablet
Other Names:
  • Abarax®
  • N-benzil-2-nitro-1-imidazolacetamide)
  • Lafepe Benznidazol
  • ABALEA®

Drug: E1224 Placebo
E1224 matched placebo capsules
Other Name: Placebo (for E1224)

Experimental: BZN 300 mg - 4 wks

Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks, followed by:

Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.

Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.

Drug: Benznidazole
Benznidazole tablet
Other Names:
  • Abarax®
  • N-benzil-2-nitro-1-imidazolacetamide)
  • Lafepe Benznidazol
  • ABALEA®

Drug: E1224 Placebo
E1224 matched placebo capsules
Other Name: Placebo (for E1224)

Drug: Benznidazole Placebo
Benznidazole matched placebo tablets
Other Name: Placebo (for Benznidazole)

Experimental: BZN 300 mg - 2 wks

Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 2 weeks, followed by:

Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 6 weeks.

Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.

Drug: Benznidazole
Benznidazole tablet
Other Names:
  • Abarax®
  • N-benzil-2-nitro-1-imidazolacetamide)
  • Lafepe Benznidazol
  • ABALEA®

Drug: E1224 Placebo
E1224 matched placebo capsules
Other Name: Placebo (for E1224)

Drug: Benznidazole Placebo
Benznidazole matched placebo tablets
Other Name: Placebo (for Benznidazole)

Experimental: BZN 150 mg - 4 wks

Benznidazole (100 mg and 50 mg) tablets and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in two separate daily doses for 4 weeks, followed by:

Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.

Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.

Drug: Benznidazole
Benznidazole tablet
Other Names:
  • Abarax®
  • N-benzil-2-nitro-1-imidazolacetamide)
  • Lafepe Benznidazol
  • ABALEA®

Drug: E1224 Placebo
E1224 matched placebo capsules
Other Name: Placebo (for E1224)

Drug: Benznidazole Placebo
Benznidazole matched placebo tablets
Other Name: Placebo (for Benznidazole)

Experimental: BZN 150 mg - 4 wks / E1224 300 mg

Benznidazole (100 mg and 50 mg) tablets and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in two separate daily doses for 4 weeks, followed by:

Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.

Three E1224 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks. (total dose: 3000 mg).

Drug: Benznidazole
Benznidazole tablet
Other Names:
  • Abarax®
  • N-benzil-2-nitro-1-imidazolacetamide)
  • Lafepe Benznidazol
  • ABALEA®

Drug: E1224
E1224 capsules
Other Names:
  • Fosravuconazole
  • E1224 (prodrug for active ingredient Ravuconazole)

Drug: Benznidazole Placebo
Benznidazole matched placebo tablets
Other Name: Placebo (for Benznidazole)

Experimental: BZN 300 mg (weekly) 8 wks / E1224 300 mg

Benznidazole (100 mg and 50 mg) tablets by mouth, once weekly for 8 weeks (total 8 days of intermittent treatment) and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in the other 6 days of the week for 8 weeks

Three E1224 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks. (total dose: 3000 mg).

Drug: Benznidazole
Benznidazole tablet
Other Names:
  • Abarax®
  • N-benzil-2-nitro-1-imidazolacetamide)
  • Lafepe Benznidazol
  • ABALEA®

Drug: E1224
E1224 capsules
Other Names:
  • Fosravuconazole
  • E1224 (prodrug for active ingredient Ravuconazole)

Drug: Benznidazole Placebo
Benznidazole matched placebo tablets
Other Name: Placebo (for Benznidazole)

Placebo Comparator: Placebo

Benznidazole Placebo (100 mg and 50mg) tablets by mouth, every 12 hours for 8 weeks.

Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.

Drug: E1224 Placebo
E1224 matched placebo capsules
Other Name: Placebo (for E1224)

Drug: Benznidazole Placebo
Benznidazole matched placebo tablets
Other Name: Placebo (for Benznidazole)




Primary Outcome Measures :
  1. Parasitological response as determined by serial negative qualitative PCR results (3 negative PCR results, from 3 samples to be collected in the same day) at EOT and sustained parasitological clearance until 6 months follow-up. [ Time Frame: From the end of the treatment period up to 6 months. ]

    To determine the efficacy of different dosing regimens of orally administered BZN and BZN/E1224 in individuals with chronic indeterminate CD, by determining the proportion of patients who convert from positive to negative in serial, qualitative PCR test results (3 negative PCR results) at end of treatment (EOT) and sustain parasitological clearance at 6 months of follow-up, in comparison to placebo.

    For efficacy assessments, the EOT of each treatment arm will be defined in accordance to the duration of the treatment regimen. Sustained response will be assessed in all treatment arms using the same number of PCR samples (i.e., EOT; 12 weeks; 4 and 6 months).



Secondary Outcome Measures :
  1. Incidence of Adverse Events (AEs) [ Time Frame: Through study completion, i.e up to 12 months. ]
    The safety consists the description of each serious adverse event and adverse event (preferred term) per treatment group and classified by system organ. EkG and Laboratory abnormalities will be considered as Adverse Events.

  2. Severity of Adverse Events (AEs) [ Time Frame: Through study completion, i.e up to 12 months. ]
    The safety consists the description of each serious adverse event and adverse event (preferred term) per treatment group and classified by system organ. EkG and Laboratory abnormalities will be considered as Adverse Events.

  3. Incidence of Serious Adverse Events (SAEs) and/or adverse events leading to treatment discontinuation [ Time Frame: Through study completion, i.e up to 12 months ]
  4. Sustained parasitological clearance at 12 weeks and 12 months of follow-up [ Time Frame: From the end of the treatment period up to 12 months. ]

    To assess the sustained parasitological response at week 12 and 12 months for each of the regimens, in comparison with placebo.

    To determine the efficacy of the different dosing regimens in individuals with chronic indeterminate CD, by determining the proportion of patients who convert from positive to negative in serial, qualitative PCR test results (3 negative PCR results) at EOT, in comparison with placebo.


  5. Parasite clearance as measured by qualitative PCR [ Time Frame: Weeks 1, 2, 3, 4, 6, 10, 12, and at 4, 6, and 12 months follow-up ]

    To assess the time to parasite DNA clearance (below the Quantitative Polymerase Chain Reaction (qPCR) Limit of Detection (LOD) for each of the regimens.

    To assess the time to sustained clearance of parasitemia for each of the regimens.


  6. Change in parasite load over time assessed as measured by quantitative PCR [ Time Frame: Weeks 1, 2, 3, 4, 6, 10, 12, and at 4, 6, and 12 months follow-up. ]
    To measure the reduction in parasite load at weeks 1, 2, 3, 4, 6, 10, 12 and at 4, 6 and 12 months follow-up, as measured by quantitative PCR.

  7. Serological response by conventional serology assessed at 12 months of follow up and non-conventional serology assessed at W12, 4, 6, and 12 months of follow up. (changes in titters over time) [ Time Frame: From the end of the treatment period up to 12 months. ]
    To evaluate serological response by conventional serology at 12 months of follow up and non-conventional serology at week 12, 4, 6 and 12 months of follow up.


Other Outcome Measures:
  1. Area under the plasma concentration versus time curve (AUC) of ravuconazole and benznidazole [ Time Frame: D0 (pre-dose), day 1 (post-dose), day 2, day 3, steady-state phase (week 2-10) ]
    Characterization of population pharmacokinetic parameters of orally administered BZN and BZN/E1224

  2. Peak Plasma Concentration (Cmax) of ravuconazole and benznidazole [ Time Frame: D0 (pre-dose), day 1 (post-dose), day 2, day 3, steady-state phase (week 2-10) ]
    To characterize the population pharmacokinetic parameters of orally administered BZN and BZN/E1224

  3. Minimum Plasma Concentration (Cmin) of ravuconazole and benznidazole [ Time Frame: D0 (pre-dose), day 1 (post-dose), day 2, day 3, steady-state phase (week 2-10) ]
    To characterize the population pharmacokinetic parameters of orally administered BZN and BZN/E1224

  4. Clearance of ravuconazole and benznidazole [ Time Frame: D0 (pre-dose), day 1 (post-dose), day 2, day 3, steady-state phase (week 2-10) ]
    To characterize the population pharmacokinetic parameters of orally administered BZN and BZN/E1224

  5. Volume of Distribution of ravuconazole and benznidazole [ Time Frame: D0 (pre-dose), day 1 (post-dose), day 2, day 3, steady-state phase (week 2-10) ]
    To characterize the population pharmacokinetic parameters of orally administered BZN and BZN/E1224

  6. Plasma Terminal Half-Life (t1/2) of ravuconazole and benznidazole [ Time Frame: D0 (pre-dose), day 1 (post-dose), day 2, day 3, steady-state phase (week 2-10) ]
    To characterize the population pharmacokinetic parameters of orally administered BZN and BZN/E1224



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Screening criteria

  • Signed, written informed consent form
  • Age >18 to <50 years
  • Weight >50 kg to <80 kg
  • Diagnosis of T. cruzi infection by: Conventional serology (a minimum of two positive tests [Conventional ELISA, Recombinant Elisa and/or Indirect Immunofluorescence (IIF)])
  • Ability to comply with all protocol specified tests and visits and have a permanent address
  • Patients must be residents of areas free of vectorial transmission (Triatoma infestans). For this protocol, it will be accepted the status of Vectorial Transmission Interruption or Consolidation as per the definition of PAHO/WHO, or the Local Health Program.
  • No signs and/or symptoms of the chronic cardiac and/or digestive form of CD
  • No acute or chronic health conditions, that in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the trial drug (such as acute infections, history of HIV infection, liver and renal disease requiring treatment)
  • No formal contraindication to BZN (according to the Summary of Product Characteristics) and E1224 (according to the Investigator's Brochure) Note: The contraindications described for Benznidazole and E1224 are essentially hypersensitivity to the active ingredient or any excipient. In the case of hepatic or renal impairment or blood dyscrasia, the medication should only be administered under strict medical supervision. During all the treatment period, the blood count will be monitored, with special attention to leucocytes. Subjects will be indicated about the need of no alcohol intake.
  • No history of hypersensitivity, allergic, or serious adverse reactions to any of the "azoles" compound, and/or its components
  • 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
  • No history of alcohol abuse or any other drug addiction (as specified in the Study Manual of Operations)
  • No condition that prevents patient from taking oral medication
  • No concomitant or anticipated use of drugs that are either sensitive CYP3A4 substrates and/or extensively metabolized by CYP3A4 with a narrow therapeutic range (as per Appendix 2)
  • No medical history of Familial Short QT syndrome or concomitant therapy with medications that can shorten the QT interval (as per Appendix 2)
  • No family history of sudden death
  • No family history of sudden infant death syndrome

Inclusion criteria

Following the screening period, patients must meet ALL of the following inclusion criteria to be eligible for randomization:

  • 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 positive tests must be positive [Conventional ELISA, Recombinant Elisa and/or IIF)
  • Women in reproductive age must have a negative serum pregnancy test at screening, must not be breastfeeding, and must use a double barrier method of contraception to avoid pregnancy throughout a clinical trial and for 3 months after completion of the trial, in such a manner that the risk of pregnancy is minimized especially during exposure to treatment. Women who are using oral, implanted, or injectable contraceptive hormones or mechanical products such as an intrauterine device with a hormonal component are required to use an additional barrier method of contraception for the time period specified.
  • Normal EKG (PR ≤200 msec, QRS <120 msec, and QTc ≥350 msec and ≤450 msec interval durations in males and QTc ≤470 msec in women) at screening.

Exclusion criteria

The presence of any of the following will exclude a patient from trial randomization:

  • Signs and/or symptoms of chronic cardiac and/or digestive form of CD
  • History of cardiomyopathy, heart failure, or ventricular arrhythmia.
  • History of digestive surgery or mega syndromes.
  • 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 trial drug (such as acute infections, history of HIV infection, diabetes, uncontrolled systolic/diastolic blood pressure, liver, and renal disease requiring medical treatment).
  • Laboratory test values considered clinically significant or out of the allowable range at selection period 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.
  • Fasting glucose must be within the normal range
  • Electrolytes (Ca, Mg, K) must be within the normal range
  • If the results of the blood tests (hematology and biochemistry) are out of the ranges defined above, but within the limits of CTCAE (version 4.03) Grade 1, and the laboratory finding is considered as non-clinically significant, a new sample can be collected for a retest. Only one retest will be allowed within the screening period.
  • If the result of retest is within the margins defined above, the Investigator will review the parameter(s) together with all other medical information available (medical history, clinical examinations, vital signs, etc.) and upon his/her medical judgment will decide if the patient is eligible or not for trial randomization.
  • Any condition that prevents the patient from taking oral medication
  • Patients with history of allergy (serious or not), allergic skin rash, asthma, intolerance, sensitivity or photosensitivity to any drug
  • Patients with any contra-indication (known hypersensitivity) to any nitroimidazoles, e.g. metronidazole.
  • Any concomitant use of allopurinol, antimicrobial, or anti-parasitic agents.
  • Any planned surgery likely to interfere with the trial conduction and/or treatment evaluation
  • Unlikely to co-operate with the trial
  • Any previous participation in any clinical trial for Chagas Disease treatment evaluation
  • Participation in another trial at the same time or within 3 months prior to selection (according to local regulations)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03378661


Locations
Bolivia
Plataforma de Atención Integral de Pacientes con Enfermedad de Chagas.
Sucre, Chuquisaca, Bolivia
Plataforma de Atención Integral de Pacientes con Enfermedad de Chagas.
Cochabamba, Bolivia
Plataforma de Atención Integral de Pacientes con Enfermedad de Chagas.
Tarija, Bolivia
Sponsors and Collaborators
Drugs for Neglected Diseases
Investigators
Principal Investigator: Faustino Torrico, PhD Plataforma de Atención Integral de Pacientes con Enfermedad de Chagas. Cochabamba, Bolivia.
Principal Investigator: Joaquim Gascón, PhD Centro de Salud Internacional, Hospital Clínico de Barcelona CRESIB - Centre de Recerca en Salut Internacional de Barcelona Barcelona, España.

Responsible Party: Drugs for Neglected Diseases
ClinicalTrials.gov Identifier: NCT03378661     History of Changes
Other Study ID Numbers: DNDi-CH-E1224-003
First Posted: December 20, 2017    Key Record Dates
Last Update Posted: December 20, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Drugs for Neglected Diseases:
Chronic, Indeterminate

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