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Chagas' DiseasePhase 4Pop PK ChagasNCT01549236

Population Pharmacokinetics Study of Benznidazole in Children With Chagas'Disease

A Phase 4 study testing Benznidazole 12,5mg or 100mg in people with Chagas' Disease, run by Drugs for Neglected Diseases at 3 sites in Argentina.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to describe the population pharmacokinetics parameters of benznidazole in children with acute or early chronic indeterminate form of Chagas Disease. Read more about this study

Who is it for?
Ages 1 day to 12 years
Conditions the study is for
Chagas' Disease
What is being tested?
Benznidazole 12,5mg or 100mg
Type of treatment
Pill or oral medicine
How many people
80 participants
Where
3 sitesArgentina
Study dates
May 2011to Oct 2012
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 day to 12 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Age between newborn (1day) - 12 years
  • Diagnosis of T. cruzi infection by:
  • Direct microscopic examination or
  • Conventional serology, at least two positive tests (ELISA, IIF or HAI)
  • Written informed consent form by parent/ legal representative
  • Children assent if > 7 years

Who cannot join

  • Pre-term (< 37 weeks gestational age) or weight < 2500 g
  • Female subject who has reached menarche
  • Subjects presenting any other acute or chronic health conditions, that in the opinion of the PI, may interfere with the PK, efficacy and/or safety evaluation of the study drug
  • Known history of hypersensitivity or serious adverse reactions to nitro- imidazoles
  • History of CD treatment with benznidazole or nifurtimox in the past
  • Immunocompromised patients (clinical history compatible with HIV infection, primary immunodeficiency or prolonged treatment with corticosteroids or other immunosuppressive drugs)
Show all 10Show fewer
  • Abnormal laboratory test values at screening for the following parameters: total WBC count, platelet count, ALT, AST, total bilirubin and creatinine.
  • Exception for this criterion is considered for newborns with congenital Chagas Disease, for whom ALT/AST and bilirubin will not be considered exclusion criteria unless considered clinically significant by the investigator.
  • Inability to comply with follow-up and/or not having a permanent address
  • Any condition that prevents the subject from taking oral medication

Trial locations and contacts

3 sites in 1 country.

Argentina3 sites

  • Hospital General de Niños Ricardo Gutierrez

    Buenos Aires, C1425

  • Hospital Público Materno Infantil

    Salta, CP3400

  • Hospital de Niños "Doctor Héctor Quintana"

    San Salvador de Jujuy, CP4600

Other trials in Argentina

About this study

The purpose of this study is to describe the population pharmacokinetics parameters of benznidazole in children with acute or early chronic indeterminate form of Chagas Disease.

Read the detailed description

Treatment of Chagas disease (CD) has been always focused on pediatric population. Initially, treatment was recommended only to acute and congenital cases (including newborns diagnosed at birth), with good parasitological response of 60% to 85% of patients in the acute phase and more than 90% of congenitally infected infants treated in the first year of life.

Despite existing treatment recommendations for children with CD (from birth to 12y), there is no formulation available that meets the needs of target pediatric population, especially the younger age groups. Benznidazole (Bz), developed over 30 years ago and the main drug of choice, is only available in an 'adult' tablet strength of 100 mg (LAFEPE Benznidazol®).

With the lack of pediatric formulation, the 100mg tablet needs to be fractionated in ½ and ¼ tablets or prepared as extemporaneous formulations (macerated, diluted, suspension, etc) to adjust the dose to patient weight, often leading to sub or over-dosing, which may affect safety and efficacy of the treatment. With regards to children, there is an absolute lack of information on Bz PK in the pediatric population and its relationship with treatment safety and efficacy.

In order to respond to the need of a age-adapted, easy to use pediatric formulation, DNDi and LAFEPE have joined efforts to develop a 12.5 mg dispersible Bz tablet targeting treatment of CD in children < 20 Kg. Once this formulation is available, two pharmacokinetics studies are planned to be conducted: a comparative bioavailability study in adult healthy normal volunteers and a population pharmacokinetics study in young children.

The group of newborns, from birth to - 2 years-old children, has been included as they represent the population of congenital cases. Current estimates of positive serology for CD in women at reproductive age vary considerably from country-to-country ranging from 5-40%, with vertical transmission rates of up to 12%. There is consensus that congenital infection may remain an important mode of transmission for another generation, and appropriate treatment targeting newborns is a possible control strategy (with very high chances of cure) with the new pediatric formulation.

Children 2-12 years-old have also been included as a target population, to represent those who may have been infected via congenital or vector-borne transmission, and usually present with the early chronic indeterminate form of the disease. In CD endemic countries these groups of children are usually diagnosed through school or community screening programs, and also have a high chance of cure (> 60-75%) with Bz treatment.

Population PK has been chosen as the study design as it would minimise the number of samples per patient, an important requirement for studies conducted in the pediatric population. The dearth of PK data in adults and lack of information on the variability in the target population does not allow for power calculations and the use of optimal sampling design for definition of the timing of samples. Experts reviewed the available information and recommended sparse sampling, with 5 PK samples distributed over the absorption phase (1 sample), steady-state (2 samples) and elimination phase (2 samples). With a total of 5 PK measurements per patient and a total of 80 patients stratified by age, it is expected that PK curves and variability can be drawn with an adequate level of precision.

PK data obtained from this study is expected to inform an age-adapted Bz regimen for the pediatric population affected by CD.

Conditions
Chagas' Disease
Being tested
Benznidazole 12,5mg or 100mg
Keywords
Chagas Disease, Trypanosoma Cruzi, T.Cruzi
Medical subject headings
Chagas Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Benznidazole 12,5mg or 100mgDrug

    Also called BNZ

    All 80 subjects recruited into the study will receive treatment with:

    • Benznidazole (Laboratório Farmacêutico do Estado de Pernambuco -LAFEPE - Recife - Brazil; tablet 12.5mg or 100mg), 7.5 mg/Kg/day PO (actual range of 5.5-8.5 mg/Kg/d), divided in two daily doses, for 60 days.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Pharmacokinetics Endpoints

    Plasma level concentrations of benznidazol determined in children at first day of treatment (Day 0), steady state phase (D7 and Day 30) and at the end of treatment (Day 60).

    Population pharmacokinetics parameters of benznidazole in children, including CL, Vd, and Ka.

    Individual AUC.

    Individual Cmax.

    Individual Cmin.

    Individual t1/2 will be estimated using population parameters.

    Measured: Day 60

Secondary outcomes (3)

  1. Efficacy Endpoints

    Parasitological cure rate as determined by qualitative PCR at the end of treatment (Day 60).

    Measured: Day 60

  2. Safety endpoints

    Rate of Serious of Adverse Events and/or adverse events leading to treatment discontinuation.

    Measured: Day 60

  3. Safety Endpoints

    Rate and severity of adverse events.

    Covariates to be evaluated: age, gender, weight, height, parasite load at baseline and phase of disease (acute vs chronic).

    Measured: Day 60

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Mar 2012 (estimated)
  2. Study startMay 2011
  3. Primary completionAug 2012
  4. Study completionOct 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
80 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01549236
Sponsor's protocol ID
DNDi-CD-PEDBZ-001
Acronym
Pop PK Chagas
Status last verified
Aug 2012
First submitted
1 Mar 2012
Last updated
25 Jun 2018
Results posted
No
Data monitoring committee
No

Publications

  • Andrade AL, Martelli CM, Oliveira RM, Silva SA, Aires AI, Soussumi LM, Covas DT, Silva LS, Andrade JG, Travassos LR, Almeida IC. Short report: benznidazole efficacy among Trypanosoma cruzi-infected adolescents after a six-year follow-up. Am J Trop Med Hyg. 2004 Nov;71(5):594-7.

    PubMed 15569790

  • de Andrade AL, Zicker F, de Oliveira RM, Almeida Silva S, Luquetti A, Travassos LR, Almeida IC, de Andrade SS, de Andrade JG, Martelli CM. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet. 1996 Nov 23;348(9039):1407-13. doi: 10.1016/s0140-6736(96)04128-1.

    PubMed 8937280

  • Sosa-Estani S, Segura EL. Etiological treatment in patients infected by Trypanosoma cruzi: experiences in Argentina. Curr Opin Infect Dis. 2006 Dec;19(6):583-7. doi: 10.1097/01.qco.0000247592.21295.a5.

    PubMed 17075335

  • Ribeiro I, Sevcsik AM, Alves F, Diap G, Don R, Harhay MO, Chang S, Pecoul B. New, improved treatments for Chagas disease: from the R&D pipeline to the patients. PLoS Negl Trop Dis. 2009 Jul 7;3(7):e484. doi: 10.1371/journal.pntd.0000484. No abstract available.

    PubMed 19582163

  • Garcia-Bournissen F, Altcheh J, Giglio N, Mastrantonio G, Della Vedova CO, Koren G. Pediatric clinical pharmacology studies in Chagas disease: focus on Argentina. Paediatr Drugs. 2009;11(1):33-7. doi: 10.2165/0148581-200911010-00012.

    PubMed 19127950

  • Altcheh J, Moscatelli G, Caruso M, Moroni S, Bisio M, Miranda MR, Monla C, Vaina M, Valdez M, Moran L, Ramirez T, Patino OL, Riarte A, Gonzalez N, Fernandes J, Alves F, Ribeiro I, Garcia-Bournissen F. Population pharmacokinetics of benznidazole in neonates, infants and children using a new pediatric formulation. PLoS Negl Trop Dis. 2023 May 31;17(5):e0010850. doi: 10.1371/journal.pntd.0010850. eCollection 2023 May.

    PubMed 37256863

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Benznidazole 12,5mg or 100mg in people with Chagas' Disease, run by Drugs for Neglected Diseases at 3 sites in Argentina.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Argentina. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Pharmacokinetics Endpoints (time frame: Day 60). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01549236, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jun 2018.

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