Short-course Benznidazole Treatment to Reduce Trypanosoma Cruzi Parasitic Load in Women of Reproductive Age

NCT03672487 — Phase 3, Completed, 87 participants, Tulane University School of Public Health and Tropical Medicine

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Short-course Benznidazole Treatment to Reduce Trypanosoma Cruzi Parasitic Load in Women of Reproductive Age: A Non-inferiority Randomized Controlled Trial

Registry	NCT03672487, acronym BETTY
Status	Completed
Phase	Phase 3
Study type	Interventional; randomized, parallel, masking: quadruple, treatment
Enrollment	87 (Actual)
Sponsor	Tulane University School of Public Health and Tropical Medicine (Other); collaborators: Institute for Clinical Effectiveness and Health Policy, University of California, San Diego
Conditions	Chagas Disease
Interventions	Benznidazole, Placebo Oral Tablet (Drug)
Dates	start 2019-06-01, primary completion 2024-05-31, completion 2025-05-31, first posted 2018-09-14, last updated 2026-04-09
Locations	3 sites in United States, Argentina

-Summary

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.

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+Arms and interventions

Arm	Type	Interventions	Description
60/300mg	Active comparator	Drug: Benznidazole	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.
30/150mg	Experimental	Drug: Benznidazole; Drug: Placebo Oral Tablet	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.

Benznidazole (Drug), also known as Abarax: Benznidazole tablet
Placebo Oral Tablet (Drug), also known as Placebo (for Benznidazole): Sugar pill manufactured to mimic Benznidazole

+Outcome measures

Primary outcomes

Global PCR (Conventional PCR and Real-time Quantitative PCR) Immediately After the End of Treatment. [Immediately after the end of treatment: 30 days for the 30-day arm, and 60 days for the 60-day arm.]: Number of participants with at least one of the four conventional and/or one of the four quantitative PCR tests positive.
Global PCR (Conventional PCR and Real-time Quantitative PCR) at 10 Months After the End of the 60-day Treatment Period. [10 months after the end of the 60-day treatment period.]: Number of participants with at least one of the four conventional and/or one of the four quantitative PCR tests positive.

Secondary outcomes

Serious Adverse Events and/or Any Adverse Event Leading to Treatment Discontinuation. [Randomization until last visit (10 months after the end of treatment or early termination).]
Median Parasitic Load by qPCR Immediately After the End of Treatment in Detectable Samples. [Immediately after the end of treatment.]: Parasitic equivalents/mL.
Median Parasitic Load by qPCR at 10 Months From the End of the 60-day Treatment Period in Detectable Samples [10 months from the end of the 60-day treatment period.]: Parasitic equivalents/mL.

+Eligibility

Sex: Female, ages: 13 Years to any, accepts healthy volunteers

Inclusion Criteria:

* Written informed consent from the mother.
* T. cruzi seropositivity confirmed by at least two positive tests.
* Live birth.

Exclusion Criteria:

* Women residing outside of the provinces of Chaco, Santiago del Estero, or Tucumán.
* Previous trypanocide treatment (BZN or nifurtimox).
* Female sterilization; no intention to use modern contraception methods during treatment.
* Positive pregnancy test.
* History of severe alcohol abuse within two years; renal insufficiency.

+Posted results

Participant flow

Milestone	60/300mg	30/150mg
Started	44	43
Completed	25	34
Not completed	19	9

Outcome results

Global PCR (Conventional PCR and Real-time Quantitative PCR) Immediately After the End of Treatment. (Primary), Count of participants, Participants: 60-day Treatment 16; 30-day Treatment 20
Global PCR (Conventional PCR and Real-time Quantitative PCR) at 10 Months After the End of the 60-day Treatment Period. (Primary), Count of participants, Participants: 60/300mg 14; 30/150mg 17
Serious Adverse Events and/or Any Adverse Event Leading to Treatment Discontinuation. (Secondary), Count of participants, Participants: 60-day Treatment 13; 30-day Treatment 8 (p 0.025)
Median Parasitic Load by qPCR Immediately After the End of Treatment in Detectable Samples. (Secondary), Median, Parasitic equivalents/mL: 60/300mg NA (NA to NA); 30/150mg 0.2 (0.2 to 0.5)
Median Parasitic Load by qPCR at 10 Months From the End of the 60-day Treatment Period in Detectable Samples (Secondary), Median, Parasitic equivalents/mL.: 60/300mg 0 (0 to 0.2); 30/150mg 0 (0 to 0)

Adverse events

Time frame: Randomization until last visit (10 months after the end of treatment or early termination).

Arm	Deaths	Serious adverse events	Other adverse events
60/300mg	0/44 (0.0%)	0/44 (0.0%)	32/44 (72.7%)
30/150mg	0/43 (0.0%)	0/43 (0.0%)	31/43 (72.1%)

Other adverse events by term

Term	Organ system	60/300mg	30/150mg
Pruritus or erythema	Skin and subcutaneous tissue disorders	21/44	15/43
Headache. dizziness, somnolence	Nervous system disorders	10/44	8/43
Gastrointestinal	Gastrointestinal disorders	12/44	11/43
Blood disorders	Blood and lymphatic system disorders	3/44	5/43
Circulatory	Cardiac disorders	1/44	1/43
Respiratory	Respiratory, thoracic and mediastinal disorders	1/44	1/43

+Locations (3)

Facility	City	Country
University of California at San Diego	San Diego, California	United States
Tulane School of Public Health and Tropical Medicine	New Orleans, Louisiana	United States
Institute for Clinical Effectiveness and Health Policy	Buenos Aires	Argentina

+Publications

Results publication: Cafferata ML, Toscani MA, Althabe F, Belizan JM, Bergel E, Berrueta M, Capparelli EV, Ciganda A, Danesi E, Dumonteil E, Gibbons L, Gulayin PE, Herrera C, Momper JD, Rossi S, Shaffer JG, Schijman AG, Sosa-Estani S, Stella CB, Klein K, Buekens P. Short-course Benznidazole treatment to reduce Trypanosoma cruzi parasitic load in women of reproductive age (BETTY): a non-inferiority randomized controlled trial study protocol. Reprod Health. 2020 Aug 24;17(1):128. doi: 10.1186/s12978-020-00972-1. PMID 32831069

+Study documents

Study Protocol and Statistical Analysis Plan (PDF, 2018-04-20)

+Investigators

Pierre Buekens, MD, PhD, Principal investigator, Tulane University

My Notes

Public

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