BENDITA BEnznidazole New Doses Improved Treatment and Associations

NCT03378661 | Unknown Phase 2 DMC

• 1 other identifier: DNDi-CH-E1224-003
• Study Type: interventional
• Target: 210
• Locations: 1 country
• Sites: 3

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.

Conditions

Chagas Disease

Keywords

Chronic, Indeterminate

Outcome Measures

Primary Outcomes (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.

  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).

  From the end of the treatment period up to 6 months.

Secondary Outcomes (7)

• Incidence of Adverse Events (AEs)

  Through study completion, i.e up to 12 months.

• Severity of Adverse Events (AEs)

  Through study completion, i.e up to 12 months.

• Incidence of Serious Adverse Events (SAEs) and/or adverse events leading to treatment discontinuation

  Through study completion, i.e up to 12 months

• Sustained parasitological clearance at 12 weeks and 12 months of follow-up

  From the end of the treatment period up to 12 months.

• Parasite clearance as measured by qualitative PCR

  Weeks 1, 2, 3, 4, 6, 10, 12, and at 4, 6, and 12 months follow-up

Other Outcomes (6)

• Area under the plasma concentration versus time curve (AUC) of ravuconazole and benznidazole

  D0 (pre-dose), day 1 (post-dose), day 2, day 3, steady-state phase (week 2-10)

• Peak Plasma Concentration (Cmax) of ravuconazole and benznidazole

  D0 (pre-dose), day 1 (post-dose), day 2, day 3, steady-state phase (week 2-10)

• Minimum Plasma Concentration (Cmin) of ravuconazole and benznidazole

  D0 (pre-dose), day 1 (post-dose), day 2, day 3, steady-state phase (week 2-10)

Study Arms (7)

BZN STD Regimen

EXPERIMENTAL

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; Drug: E1224 Placebo

BZN 300 mg - 4 wks

EXPERIMENTAL

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; Drug: E1224 Placebo; Drug: Benznidazole Placebo

BZN 300 mg - 2 wks

EXPERIMENTAL

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; Drug: E1224 Placebo; Drug: Benznidazole Placebo

BZN 150 mg - 4 wks

EXPERIMENTAL

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; Drug: E1224 Placebo; Drug: Benznidazole Placebo

BZN 150 mg - 4 wks / E1224 300 mg

EXPERIMENTAL

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; Drug: E1224; Drug: Benznidazole Placebo

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

EXPERIMENTAL

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; Drug: E1224; Drug: Benznidazole Placebo

Placebo

PLACEBO COMPARATOR

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; Drug: Benznidazole Placebo

Interventions

Benznidazole DRUG

Benznidazole tablet

Also known as: Abarax®, N-benzil-2-nitro-1-imidazolacetamide), Lafepe Benznidazol, ABALEA®

BZN 150 mg - 4 wks; BZN 150 mg - 4 wks / E1224 300 mg; BZN 300 mg (weekly) 8 wks / E1224 300 mg; BZN 300 mg - 2 wks; BZN 300 mg - 4 wks; BZN STD Regimen

E1224 DRUG

E1224 capsules

Also known as: Fosravuconazole, E1224 (prodrug for active ingredient Ravuconazole)

BZN 150 mg - 4 wks / E1224 300 mg; BZN 300 mg (weekly) 8 wks / E1224 300 mg

E1224 Placebo DRUG

E1224 matched placebo capsules

Also known as: Placebo (for E1224)

BZN 150 mg - 4 wks; BZN 300 mg - 2 wks; BZN 300 mg - 4 wks; BZN STD Regimen; Placebo

Benznidazole Placebo DRUG

Benznidazole matched placebo tablets

Also known as: Placebo (for Benznidazole)

BZN 150 mg - 4 wks; BZN 150 mg - 4 wks / E1224 300 mg; BZN 300 mg (weekly) 8 wks / E1224 300 mg; BZN 300 mg - 2 wks; BZN 300 mg - 4 wks; Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Drugs for Neglected Diseases: lead

Study Sites (3)

Plataforma de Atención Integral de Pacientes con Enfermedad de Chagas.

Sucre, Chuquisaca Department, Bolivia

Location

Plataforma de Atención Integral de Pacientes con Enfermedad de Chagas.

Cochabamba, Bolivia

Location

Plataforma de Atención Integral de Pacientes con Enfermedad de Chagas.

Tarija, Bolivia

Location

Related Publications (2)

• Saade U, de Boer J, Scandale I, Altcheh J, Pottel H, Chatelain E, Zrein M. Early assessment of antibodies decline in Chagas patients following treatment using a serological multiplex immunoassay. Nat Commun. 2024 Dec 3;15(1):10530. doi: 10.1038/s41467-024-54910-x.

  PMID: 39627222 DERIVED

• Torrico F, Gascon J, Barreira F, Blum B, Almeida IC, Alonso-Vega C, Barboza T, Bilbe G, Correia E, Garcia W, Ortiz L, Parrado R, Ramirez JC, Ribeiro I, Strub-Wourgaft N, Vaillant M, Sosa-Estani S; BENDITA study group. New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial. Lancet Infect Dis. 2021 Aug;21(8):1129-1140. doi: 10.1016/S1473-3099(20)30844-6. Epub 2021 Apr 6.

  PMID: 33836161 DERIVED

MeSH Terms

Conditions

Chagas Disease; Bronchiolitis Obliterans Syndrome

Interventions

benzonidazole; fosravuconazole L-lysine ethanolate; Prodrugs

Condition Hierarchy (Ancestors)

Trypanosomiasis; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pharmaceutical Preparations

Study Officials

• 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.

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double Dummy
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Parallel Assignment

Study Record Dates

• First Submitted: November 23, 2017
• First Posted: December 20, 2017
• Study Start: November 30, 2016
• Primary Completion: January 28, 2018
• Study Completion: July 27, 2018
• Last Updated: December 20, 2017

Record last verified: 2017-12

Data Sharing

• IPD Sharing: Will not share

Locations

BO (3)