Short-course Benznidazole for Chagas Disease

(BETTY Trial)

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

273 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Benznidazole for Chagas Disease?

Benznidazole is effective for treating the acute stage of Chagas disease, and it has shown some benefits in reducing mortality and cardiac issues in chronic cases, although its effectiveness in chronic stages is still uncertain. ^{1 2 3 4 5}

Is short-course Benznidazole safe for humans?

Benznidazole has been studied for safety in humans, and while it is generally used for treating Chagas disease, it can cause side effects. Common side effects include skin reactions and digestive issues, and some patients may experience more serious effects like neuropathy (nerve damage) and angioedema (swelling). ^{3 6 7 8 9}

What makes the drug benznidazole unique for treating Chagas disease?

Benznidazole is unique for treating Chagas disease because it is specifically designed for repeat dose schedules, ensuring stable drug levels in the body, and is the primary drug of choice despite modest cure rates and common adverse reactions. ^{3 6 7 10 11}

What is the purpose of this trial?

The investigators are proposing to perform a double-blinded, non-inferiority randomized controlled trial comparing a short 30-day treatment with BZN 150mg/day (30d/150mg) vs. a 60-day treatment with BZN 300 mg/day (60d/300mg). The investigators will recruit not previously treated T. cruzi seropositive women with a live birth during the postpartum period in Argentina, randomize them at six months postpartum, and follow them up with the following specific aims: Specific Aim 1: To measure the effect of BZN 30d/150mg compared to 60d/300mg preconceptional treatment on parasitic load measured by the frequency of positive PCR (primary outcome) and by real-time quantitative PCR (qPCR), immediately (Specific Aim 1a) and 10 months (Specific Aim 1b) after treatment. Hypothesis 1a: The frequency of positive PCR and the parasitic load measured by qPCR immediately after BZN 30d/150mg will be non-inferior (Non Inferiority \[NI\] margin for PCR: 10% absolute difference) to BZN 60d/300mg. Hypothesis 1b: The frequency of positive PCR and the parasitic load measured by qPCR 10 months after BZN 30d/150mg will be non-inferior (NI margin for PCR: 9% absolute difference) to BZN 60d/300mg. Specific Aim 2: To measure the frequency of serious adverse events leading to treatment interruption of BZN 30d/150mg compared to 60d/300mg. Hypothesis 2: The frequency of serious adverse events leading to treatment interruption will be 50% lower with BZN 30d/150mg than with BZN 60d/300mg. A 24-month recruitment period is planned in four hospitals with 23,436 deliveries in 2015 and frequencies of T. cruzi seropositive women varying from 1.5% to 4.8%. The investigators are planning to enroll 600 T. cruzi seropositive women.

Research Team

Pierre Buekens, MD, PhD

Principal Investigator

Tulane University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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 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]

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 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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Benznidazole and Posaconazole in Eliminating Parasites in Asymptomatic T. Cruzi Carriers: The STOP-CHAGAS Trial. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. [2022]

3. England 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Beneficial effects of benznidazole in Chagas disease: NIH SaMi-Trop cohort study. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Safety of benznidazole use in the treatment of chronic Chagas' disease. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Evaluation of the mutagenic potential of the antichagasic drug Rochagan in healthy and chagasic rodents. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

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

8. Spain pubmed.ncbi.nlm.nih.gov

Side effects of benznidazole treatment in a cohort of patients with Chagas disease in non-endemic country. [2015]

9. United States pubmed.ncbi.nlm.nih.gov

Tolerance of benznidazole in a United States Chagas Disease clinic. [2022]

10. Brazil pubmed.ncbi.nlm.nih.gov

Characterization of adverse reactions to benznidazole in patients with Chagas disease in the Federal District, Brazil. [2023]

11. England 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. [2023]