Shorter Benznidazole Regimens Compared to the Standard Regimen for Chagas Disease

Phase III Randomized,Multicenter Non-inferiority Study to Evaluate the Efficacy and Safety of Shorter Benznidazole Regimens Compared to the Standard Regimen to Treat Adult Patients With Chronic Chagas Disease

Chagas disease, a parasitic infection caused by Trypanosoma cruzi, is endemic in much of Latin America and affects people throughout the world. Currently treatment with the only two drugs effective against the infection, benznidazole and nifurtimox, has significant limitations including frequent adverse effects in adult patients. However, timely treatment is key to achieving global objectives of controlling the disease. The standard treatment has a long duration (60 days). NuestroBen will test the hypothesis that shorter treatment regimens of 14 days and 28 days will be non-inferior to the standard 60-day treatment while improving the safety profile.

Chagas disease is a vector-borne parasitic infection affecting an estimated 6 million people worldwide. Very few people have been able to access antiparasitic treatment for the disease, and about 20% of those who do initiate treatment are unable to complete it due to the long duration (2 months) and side effects associated with the current regimen. Benznidazole is one of only two drugs with proven efficacy against Trypanosoma cruzi, the parasite that causes the disease. An earlier Phase 2 clinical trial, BENDITA, indicated 89% of 30 patients treated with a shorter (2-week) regimen of benznidazole maintained sustained parasite clearance after 12 months of follow-up, with no discontinuations of treatment due to side effects. The current study will evaluate shorter treatment regimens with benznidazole in a Phase III clinical trial. NuestroBen will assess the efficacy and safety of 2-week and 4-week regimens of BZN (300 mg daily), compared to the standard treatment of BZN 300 mg daily for 8 weeks, in terms of reducing and eliminating the T. cruzi parasite in adults in the chronic phase of Chagas disease with the indeterminate form or mild cardiac progression. Efficacy will be measured through conversion from positive to negative parasitaemia according to the results of qualitative PCR tests from the end of treatment, and up to 12 months of follow-up from the end of treatment. Safety will be compared according to the frequency and severity of adverse events. Patients adherence to treatment in each study arm will also be described.

Inclusion criteria (Subjects must meet ALL the inclusion requirements listed below to enter the study):

• Signed informed consent form;
• Between ≥18 and ≤60 years of age;
• Weight ≥ 50 kg to ≤ 95 kg;
• Confirmation of the diagnosis of T. cruzi infection by conventional serology (a minimum of two tests must be reactive);
• Serial qualitative PCR (one blood sample divided in three DNA extractions, at least one of which must be positive);
• Women of childbearing potential must have a negative pregnancy result at the time of inclusion, must not be breast-feeding, and must use a highly effective method of contraception during study treatment and until 30 days after the last dose of study treatment or demonstrate permanent sterilization;
• Ability to comply with all exams and specific protocol visits;
• Having a permanent address;
• ECG criteria: (Heart rate: 50 -100 bpm or isolate sinus bradycardia from 41 to 59 beats/min; QRS ≤120 msec, and QTc ≥ 350 msec and ≤ 450 msec) at screening) or following findings belonging to non-severe chagasic cardiomyopathy: uncomplete right bundle branch block, Left anterior fascicular block, First-degree atrioventricular block, Low voltage. The abnormalities included are not exclusionary;
• Normal or minimal structural changes in echocardiogram (left ventricular diastolic diameter (LVDD) <= 55 mm, diastolic dysfunction, absence of Microaneurysm or tip aneurysm, absence of hypo or generalized akinesia, absence of Systolic dysfunction (low fractional shortening and ejection fraction), and/or absence of mural thrombus);
• Not presenting signs or symptoms of moderate- severe chronic cardiac and/or digestive forms of Chagas disease (criteria detailed in Study Manual and specific SOP);
• No prior history of mental disorders or suicidal tendencies;
• Not suffering from known acute or chronic illnesses at the moment of selection for the study that, in the Investigator's discretion, may interfere with the evaluation of the efficacy or safety of the investigational product (such as acute infections, immunosuppressive conditions, or liver or kidney diseases that have required treatment);
• Not having received a formal indication not to take BZN (contraindication, according to the Summary of Product Characteristics - SmPC);
• No prior history of hypersensitivity, allergy, or serious adverse reactions to any of the nitroimidazole compounds (including BNZ) and/or its components/excipients;
• Have not previously undergone antiparasitic treatment for T. cruzi infection;
• No prior history of drug abuse or alcoholism;
• Not suffering from any disease or condition that prevents subjects from consuming oral medication.

Exclusion criteria (The presence of any of the items below will exclude subjects from inclusion in the study):

• Subject pregnant or intending to become pregnant during treatment and within 30 days of the last dose of study treatment;
• Signs or symptoms of the established (moderate- severe) chronic cardiac and/or digestive form of Chagas disease, or any ECG/ echocardiographic findings not included at Inclusion criteria;
• History of cardiomyopathy, heart failure, or severe ventricular arrhythmia;
• History of digestive surgery potentially related to Chagas Disease or megacolon / mega-esophagus;
• Acute or chronic disease that, in the Investigator's discretion, may interfere with the evaluation of the efficacy or safety of the investigational product (such as acute infection, history of immunosuppressive conditions, or liver or kidney disease that has required treatment);
• Laboratory test values that are considered clinically significant or outside the allowable values, per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1;
• Disease or clinical condition that prevents subjects from consuming oral medication;
• Subjects with a contraindication (known hypersensitivity) to any of the nitroimidazole compounds, e.g. metronidazole;
• Subjects with a history of allergy (serious or not), allergic rash, asthma, intolerance, sensitivity or photosensitivity;
• Concomitant use and/or consumption of allopurinol, antimicrobial and antiparasitic agents, herbal medicines, dietary supplements and energy drinks;
• Scheduled surgery that may interfere with the conduct of the trial and/or with the treatment evaluation;
• Inability to attend study visits, comply with treatment, and cooperate with study procedures;
• Previous participation in a trial for the evaluation of the treatment of T. cruzi infection;
• Simultaneous participation in another trial or within 3 months prior to screening for this trial (in accordance with national regulations).
• Subjects suffering from a serious medical or psychiatric illness that increases the risk associated with study participation or that interferes with the interpretation of study results should not be included.