Short-course Benznidazole for Chagas Disease

(BETTY Trial)

Not currently recruiting at 2 trial locations

Overseen By Maria Luisa Cafferata, MD

Age: Any Age

Sex: Female

Trial Phase: Phase 3

Sponsor: Tulane University School of Public Health and Tropical Medicine

Disqualifiers: Outside provinces, Previous treatment, Pregnancy, Alcohol abuse, Renal insufficiency, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 30-60 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a shorter, less intense treatment for Chagas disease, caused by a parasite. It compares a 30-day benznidazole treatment (an antiparasitic medication) to the standard 60-day treatment to determine if the shorter course effectively reduces the parasite load. Researchers aim to assess whether the shorter treatment causes fewer serious side effects. Women in Argentina who have tested positive for the Chagas parasite and have recently given birth may be eligible to join. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that benznidazole is generally safe, though it can cause side effects. In studies, about 29% of patients experienced side effects, mostly mild to moderate, meaning they weren't too serious.

Shorter treatments with benznidazole, such as the 30-day course, have proven safer than the standard 60-day course, resulting in fewer serious side effects.

Benznidazole has long been used to treat Chagas disease, supporting its overall safety for humans. However, discussing the risks and benefits with a doctor before joining a trial is always important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment for Chagas Disease?

Researchers are excited about the short-course benznidazole treatment for Chagas disease because it offers a potentially more convenient and less burdensome option compared to the traditional 60-day regimen. Unlike the standard treatment, which requires patients to take 300 mg daily for two months, the investigational short course involves a lower dose of 150 mg per day for just 30 days. This shorter and lower-dose regimen could reduce side effects and improve patient adherence, making it a promising alternative for those affected by Chagas disease.

What evidence suggests that this treatment might be an effective treatment for Chagas Disease?

Research has shown that benznidazole effectively treats Chagas disease. One study found that a 60-day course of benznidazole was 55.8% effective in making the parasite undetectable in early chronic T. cruzi infections, significantly reducing the parasite in the body. In this trial, participants will be assigned to different treatment arms: one group will receive a 60-day course of benznidazole, while another group will receive a shorter 30-day course. The shorter treatment has also been effective in reducing the spread of Chagas disease and may cause fewer side effects, making it easier for patients to complete. While the shorter course might not completely eliminate the infection, it could offer a safer and more manageable treatment option. ^{2 6 7 8 9}

Who Is on the Research Team?

Pierre Buekens, MD, PhD

Principal Investigator

Tulane University

Are You a Good Fit for This Trial?

This trial is for women of reproductive age in Argentina who have had a live birth, are not sterilized, plan to use contraception, and have Chagas disease without prior treatment. They must consent to participate and reside in specific provinces.

Inclusion Criteria

T. cruzi seropositivity confirmed by at least two positive tests

Live birth

I have given my written consent.

Exclusion Criteria

I have been treated with BZN or nifurtimox before.

I am sterilized and do not plan to use birth control during treatment.

Positive pregnancy test

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a 30-day treatment with BZN 150mg/day or a 60-day treatment with BZN 300mg/day

30-60 days

Daily oral administration

Immediate Follow-up

Participants are monitored for parasitic load and adverse events immediately after treatment

0 weeks (immediate)

Long-term Follow-up

Participants are monitored for parasitic load 10 months after treatment

10 months

What Are the Treatments Tested in This Trial?

Interventions

• Benznidazole
• Placebo Oral Tablet

Trial Overview The study compares two Benznidazole (BZN) treatments for Chagas disease: a short 30-day course with lower dose versus the standard 60-day course with higher dose. The goal is to see if the shorter treatment reduces parasitic load as effectively without increasing serious side effects.

How Is the Trial Designed?

Group I: 30/150mg Experimental Treatment 2 Interventions

The investigators will use a preparation of benznidazole (BZN) that is commercially available in Argentina: Abarax® 100mg and 50mg tablets from ELEA laboratories (Buenos Aires, Argentina). ELEA laboratories will prepare the placebo oral tablets, which will be identical to the drug tablets in aspect and taste. The investigators will purchase the drug and placebo at full cost. Interventions: The BZN short course low dose scheme will be 150 mg per day for 30 days. The drug will be administered orally in two doses per day: the short course treatment will start with the active drug and then placebo oral tablet; one 100 mg tablet and one placebo tablet in the morning and one 50 mg tablet and one placebo tablet in the evening for the first 30 days. The last 30 days will be two placebo tablets in the morning and the evening.

Group II: 60/300mg Active Control 1 Intervention

The investigators will use a preparation of benznidazole (BZN) that is commercially available in Argentina: Abarax® 100mg and 50mg tablets from ELEA laboratories (Buenos Aires, Argentina). The investigators will purchase the drug at full cost. Interventions: The standard 60d course will be 300 mg per day, which is similar to the dose used in the second phase of the BENEFIT trial. The drug will be administered orally in two doses per day: the standard course will be one 100mg and one 50mg tablet in the morning and in the evening for 60 days.

Benznidazole is already approved in United States for the following indications:

Approved in United States as Benznidazole for:

• Chagas disease (American trypanosomiasis)

Who Is Running the Clinical Trial?

Tulane University School of Public Health and Tropical Medicine

Lead Sponsor

Trials

13

Recruited

198,000+

University of California, San Diego

Collaborator

Trials

1,215

Recruited

1,593,000+

Institute for Clinical Effectiveness and Health Policy

Collaborator

Trials

18

Recruited

160,000+

Published Research Related to This Trial

In a study of 120 asymptomatic Chagas disease carriers, benznidazole monotherapy was found to be significantly more effective than posaconazole alone or in combination, achieving an 86.7% negative RT-PCR rate by day 180 compared to only 10% for posaconazole.

While posaconazole showed some short-term effectiveness, it did not provide long-term benefits, and the combination therapy did not outperform benznidazole alone, indicating that benznidazole remains the superior treatment option for eliminating T. cruzi parasites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benznidazole and Posaconazole in Eliminating Parasites in Asymptomatic T. Cruzi Carriers: The STOP-CHAGAS Trial. Morillo, CA., Waskin, H., Sosa-Estani, S., et al.[2022]

In a study of 190 adult patients with chronic Chagas' disease treated with benznidazole for an average of about 59 days, 49% experienced adverse drug reactions (ADRs), with a higher incidence in women and younger adults, particularly during the first 30 days of treatment.

Despite the occurrence of ADRs, most were mild and reversible upon stopping the medication, and there were no fatal events, indicating that benznidazole is considered a safe treatment option for chronic Chagas' disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of benznidazole use in the treatment of chronic Chagas' disease. Hasslocher-Moreno, AM., do Brasil, PE., de Sousa, AS., et al.[2022]

In a study of 62 patients treated with benznidazole for Chagas disease, 66% experienced adverse drug reactions (ADRs), leading to a significant treatment discontinuation rate of 37%.

Most ADRs were classified as severe and serious, indicating a high risk associated with benznidazole treatment, highlighting the urgent need for safer alternatives for managing Chagas disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of adverse reactions to benznidazole in patients with Chagas disease in the Federal District, Brazil. Gontijo, MKCL., Arruda, HMBDS., Noronha, EF., et al.[2023]

The MULTIBENZ trial is a phase II clinical study involving 240 patients with chronic Chagas disease across four countries, aiming to compare the efficacy and safety of different dosing regimens of benznidazole (BNZ).

The primary outcome will measure the effectiveness of BNZ in suppressing parasitic load in the blood, which could help determine the optimal dosing strategy for treating Chagas disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety assessment of different dosage of benznidazol for the treatment of Chagas disease in chronic phase in adults (MULTIBENZ study): study protocol for a multicenter randomized Phase II non-inferiority clinical trial. Molina-Morant, D., Fernández, ML., Bosch-Nicolau, P., et al.[2023]

In a study of 373 chronic Chagas disease patients treated with benznidazole, 40.2% experienced adverse reactions, highlighting the need for careful monitoring during treatment.

The most common side effects were dermatological reactions (32.4%) and digestive intolerance (9.1%), with rare cases of migratory arthritis, indicating that while benznidazole is effective, it can lead to significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects of benznidazole treatment in a cohort of patients with Chagas disease in non-endemic country. Carrilero, B., Murcia, L., Martínez-Lage, L., et al.[2015]

In a study involving 30 adults with chronic Chagas disease, benznidazole at a dosage of 5 mg/kg/day for 60 days was found to have a concerning side-effect profile, including 5 cases of debilitating neuropathy.

The treatment also showed an unusually high rate of angioedema, indicating potential safety concerns that need to be addressed when considering benznidazole for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerance of benznidazole in a United States Chagas Disease clinic. Miller, DA., Hernandez, S., Rodriguez De Armas, L., et al.[2022]

In a clinical trial involving 566 patients with nonacute Chagas disease, treatment with benznidazole significantly reduced disease progression compared to untreated patients, with only 4% of treated patients experiencing progression versus 14% in the control group.

Patients treated with benznidazole also showed a higher rate of negative serologic conversion (15% vs. 6%), indicating that the treatment may effectively reduce the disease's presence in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Viotti, R., Vigliano, C., Lococo, B., et al.[2022]

In a study of 1,959 patients with chronic Chagas disease, those treated with benznidazole showed a significantly lower mortality rate (2.8%) compared to untreated patients (7.6%) over two years, suggesting the treatment's effectiveness in improving survival.

Patients who received benznidazole also had lower rates of severe heart disease markers and reduced parasitemia, indicating that early treatment may lead to better clinical outcomes in chronic Chagas disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial effects of benznidazole in Chagas disease: NIH SaMi-Trop cohort study. Cardoso, CS., Ribeiro, ALP., Oliveira, CDL., et al.[2022]

In a study involving eight patients with Chagas disease, benznidazole was shown to have stable plasma levels during a four-week treatment, indicating its suitability for repeated dosing.

The plasma levels of benznidazole remained consistent without significant fluctuations, suggesting that it can be safely administered according to the recommended treatment schedule for Chagas disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple-dose kinetics of the trypanosomicide benznidazole in man. Raaflaub, J.[2015]

In a study involving rats and mice, acute and chronic exposure to the antichagasic drug Rochagan (benznidazole) did not result in significant chromosomal aberrations or micronuclei in bone marrow or peripheral blood cells, indicating a lack of genotoxicity.

The study involved various doses of benznidazole, with acute treatments ranging from 150 to 3000 mg/kg and chronic treatments at 100 mg/kg/day for up to 25 days, demonstrating the drug's safety profile in terms of genetic damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the mutagenic potential of the antichagasic drug Rochagan in healthy and chagasic rodents. Souza, SC., Takahashi, CS., da Silva, JS.[2019]

Antioxidant supplementation with ascorbic acid (1000 mg/day) significantly reduced adverse drug reactions (ADRs) caused by benznidazole in a patient with chronic indeterminate Chagas' disease, suggesting that oxidative stress is a key factor in the drug's toxicity.

The study indicates that monitoring oxidative stress biomarkers could help manage Chagas' disease treatment and improve patient adherence to benznidazole, highlighting the need for further research on antioxidant co-supplementation in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitigation of benznidazole toxicity and oxidative stress following ascorbic acid supplementation in an adult traveller with chronic indeterminate Chagas' disease. Van Den Broucke, S., Van Herreweghe, M., Breynaert, A., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38252673/

Efficacy of short-course treatment for prevention ... Our study demonstrated that short-duration treatment (≤30 days) is effective and beneficial in preventing transplacental transmission of Chagas disease.

2. reproductive-health-journal.biomedcentral.com reproductive-health-journal.biomedcentral.com/articles/10.1186/s12978-020-00972-1

Short-course Benznidazole treatment to reduce Trypanosoma ... A short and low dose BZN treatment might reduce major side effects and increase compliance, but its efficacy to reduce T. cruzi parasitic load compared to the ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1473309923006291

Efficacy of three benznidazole dosing strategies for adults ... Treatment with benznidazole for chronic Chagas disease is associated with low cure rates and substantial toxicity. We aimed to compare the parasitological ...

4. jacc.org jacc.org/doi/10.1016/j.jacc.2016.12.023

Benznidazole and Posaconazole in Eliminating Parasites ... Benznidazole monotherapy is superior to posaconazole, with high RT-PCR conversion rates sustained at 1 year. Side effects lead to therapy discontinuation in 32 ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0140673696041281

Randomised trial of efficacy of benznidazole in treatment ... The trial showed that a 60-day course of benznidazole treatment of early chronic T cruzi infection was safe and 55·8% effective in producing ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9135346/

Use of benznidazole to treat chronic Chagas disease The odds ratio (OR) for seroreversion in children treated with benznidazole vs P/nT was 38.3 (95%CI: 10.7–137) and 34.9 (95%CI: 1.96–624.09) in ...

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa1507574

Randomized Trial of Benznidazole for Chronic Chagas' ... The primary outcome occurred in 394 patients (27.5%) in the benznidazole group and in 414 (29.1%) in the placebo group (hazard ratio, 0.93; 95% ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04897516

Study Details | NCT04897516 | Shorter Benznidazole ... Shorter treatment regimens of 14 days and 28 days will be non-inferior to the standard 60-day treatment while improving the safety profile.

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39210623/

Adverse events associated with benznidazole treatment for ... Although 29.34% of patients experienced ADRs, most were mild to moderate, indicating a manageable safety profile for benznidazole.