See the published version of this preprint at Reproductive Health.
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Study protocol
María Luisa Cafferata
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9928-5522
License:
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Background
Retrospective observational studies suggest that transmission of the Trypanosoma cruzi does not occur in treated women when pregnant later in life. The level of parasitemia is a known risk factor for congenital transmission. Benznidazole (BZN) is the drug of choice for preconceptional treatment to reduce parasitic load. The BENEFIT trial, conducted in Argentina, compared a BZN 60-day/300 mg per day (60d/300mg) course (for subjects weighing 60kg) vs. placebo among patients with Chagas’ cardiomyopathy. The rate of conversion to negative conventional PCR (PCR) in the blood was 66.2% in the BZN group vs. 33.5% in the placebo group. Of concern, the rate of treatment interruption caused by adverse events was 23.9% in the BZN group.
The fear of treatment-related side effects limits the implementation of the Argentine guideline recommending BZN 60d/300mg (or equivalent) treatment of T. cruzi seropositive women during the postpartum period to prevent transmission in a future pregnancy. 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 standard 60d/300mg course is not yet established. Observational, animal, and pharmacokinetics (PK) studies suggest that the 60d/300mg course may be overdosing patients unnecessarily and increasing adverse events. Young and healthy subjects might have lower rates of treatment failures and adverse events. Clinical trials testing alternative BZN courses among women of reproductive age are urgently needed.
Methods and design
We are proposing to perform a double-blinded, non-inferiority randomized controlled trial comparing a short low dose 30-day treatment with BZN 150mg/day (30d/150mg) vs. BZN 60d/300mg. We 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 Polymerase Chain Reaction (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 and/or any adverse event leading to treatment interruption of BZN 30d/150mg compared to 60d/300mg.
Hypothesis 2: the frequency of serious adverse events and/or any adverse event leading to treatment interruption will be 50% lower with BZN 30d/150mg than with BZN 60d/300mg.
Trial registration: ClinicalTrials.gov. Identifier: NCT03672487. Registed 14 September 2018, https://clinicaltrials.gov/ct2/show/NCT03672487?recrs=a&cond=Chagas+Disease&cntry=AR&draw=2&rank=3
Keywords
Benznidazole, Chagas disease, preconception care, randomized controlled trial, Trypanosoma cruzi
Figure 1
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CURRENT STATUS: Published
View the published article at Reproductive Health.
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Editorial decision: Accept
On 31 Jul, 2020
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On 30 Jul, 2020
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On 29 Jul, 2020
Editor invited
On 29 Jul, 2020
Version 1
Posted 05 Jun, 2020
No comments provided
Editorial decision: Minor revision
On 16 Jun, 2020
Editor assigned
On 10 Jun, 2020
Editor invited
On 09 Jun, 2020
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On 02 Jun, 2020
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On 29 May, 2020
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Subject Areas
Sexual & Reproductive Medicine
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A new preprint design is coming!
We have improved readability, clarity, accessibility, and opportunities for engagement.
See the published version of this preprint at Reproductive Health.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Study protocol
María Luisa Cafferata
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9928-5522
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Reproductive Health.
No community comments so far
Editorial decision: Accept
On 31 Jul, 2020
Editor assigned
On 30 Jul, 2020
Submission checks complete
On 29 Jul, 2020
Editor invited
On 29 Jul, 2020
Version 1
Posted 05 Jun, 2020
No comments provided
Editorial decision: Minor revision
On 16 Jun, 2020
Editor assigned
On 10 Jun, 2020
Editor invited
On 09 Jun, 2020
Submission checks complete
On 02 Jun, 2020
First submitted
On 29 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Sexual & Reproductive Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Reproductive Health.
Background
Retrospective observational studies suggest that transmission of the Trypanosoma cruzi does not occur in treated women when pregnant later in life. The level of parasitemia is a known risk factor for congenital transmission. Benznidazole (BZN) is the drug of choice for preconceptional treatment to reduce parasitic load. The BENEFIT trial, conducted in Argentina, compared a BZN 60-day/300 mg per day (60d/300mg) course (for subjects weighing 60kg) vs. placebo among patients with Chagas’ cardiomyopathy. The rate of conversion to negative conventional PCR (PCR) in the blood was 66.2% in the BZN group vs. 33.5% in the placebo group. Of concern, the rate of treatment interruption caused by adverse events was 23.9% in the BZN group.
The fear of treatment-related side effects limits the implementation of the Argentine guideline recommending BZN 60d/300mg (or equivalent) treatment of T. cruzi seropositive women during the postpartum period to prevent transmission in a future pregnancy. 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 standard 60d/300mg course is not yet established. Observational, animal, and pharmacokinetics (PK) studies suggest that the 60d/300mg course may be overdosing patients unnecessarily and increasing adverse events. Young and healthy subjects might have lower rates of treatment failures and adverse events. Clinical trials testing alternative BZN courses among women of reproductive age are urgently needed.
Methods and design
We are proposing to perform a double-blinded, non-inferiority randomized controlled trial comparing a short low dose 30-day treatment with BZN 150mg/day (30d/150mg) vs. BZN 60d/300mg. We 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 Polymerase Chain Reaction (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 and/or any adverse event leading to treatment interruption of BZN 30d/150mg compared to 60d/300mg.
Hypothesis 2: the frequency of serious adverse events and/or any adverse event leading to treatment interruption will be 50% lower with BZN 30d/150mg than with BZN 60d/300mg.
Trial registration: ClinicalTrials.gov. Identifier: NCT03672487. Registed 14 September 2018, https://clinicaltrials.gov/ct2/show/NCT03672487?recrs=a&cond=Chagas+Disease&cntry=AR&draw=2&rank=3
Figure 1
This is a list of supplementary files associated with this preprint. Click to download.
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