Clinical trial NCT02386358: Etiologic Treatment With Benznidazole in Adult Patients With Chronic Chagas Disease. A Randomized Clinical Trial
Official title: Etiologic Treatment With Benznidazole in Adult Patients With Chronic Chagas Disease. A Randomized Double Blind Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chagas Disease
Keywords: Chronic Chagas Disease
Randomized Clinical Trial double blind
Benznidazole vs Placebo
Adult patients
Lead sponsor: Instituto Nacional de Parasitologia Dr. Mario Fatala Chaben
Sponsor class: OTHER_GOV
Collaborators: name: National Council of Scientific and Technical Research, Argentina
name: Pan American Health Organization
name: Becas Carrillo Oñativia, Ministerio de Salud, Argentina
name: Drugs for Neglected Diseases
First posted: 2015-03-11
Enrollment: 910
Sex: ALL
Minimum age (years): 20
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is:

1. -to determine whether benznidazole (BZN) will be able to modify the natural evolution of chronic Chagas disease in adult patients by means of a randomized, double-blind clinical trial (RCT).

   Also:
2. -to validate therapeutic efficacy with new methods, such as recombinant antigen F29 of Trypanosoma cruzi visualized by conventional ELISA, in the context of the RCT compared with conventional serology (CS)
3. -to develop the real-time polymerase chain-reaction (RT-PCR) to quantify the parasite load as an early therapeutic effect.
4. to determine the potential of such serological and parasitological methods as predictors of therapeutic effect or failure.

Detailed description: Patients and Methods. Patients selected to be enrolled were born in Chagas disease endemic areas of Argentina and bordering countries such as Bolivia and Paraguay, whose current residence is in urban non endemic areas of Argentina. They were sorted by clinical stage: stage 0, 1, 2 and 3 according to a modified Kuschnir classification.1 Briefly, Stage 0 corresponds to patients only with reactive serology for Chagas disease; stage 1, patients with reactive serology plus electrocardiographic abnormalities; stage 2, patients with the abovementioned characteristics plus dilatation of left ventricle by echocardiography, and stage 3, patients with the abovementioned characteristics, plus cardiac failure.

The follow-up was performed every 4 months during the first 2 years, every 6 months in the 3rd and 4th year, and annually from then on until the end of the study in 2012.

The safety of TRAENA was controlled at days 25 and 45 intra-treatment by means of laboratory tests and clinical evaluation, and at any time that an adverse event was apparent in patients.

Adherence to medication administration was verified by means of a booklet where the patient recorded the daily intake of medication and any physical abnormality that appeared during the time they were taking of medicine. Adherence was controlled by a surveillance and recovery system which consisted of telephone calls, telegrams, letters or home visits that was termed "active monitoring", which was immediately applied to the control visit when the patient did not attend the corresponding schedule control.

Telephone calls were the most useful tool to recover adherence to monitoring. Patients were assigned to BZN or Placebo treatment by an investigator independent from the research group. Prior to randomization, a pre randomization stratification was performed according to prognostic factors based on clinical stages of Chagas disease.

A database was designed to be used as the registry for the whole study. Demographic, epidemiologic, serologic, parasitological and clinical variables were used in its design, and were registered pre treatment, intra treatment and post treatment throughout the monitoring. Medical records were the primary documents for the registry, where all the variables were recorded manually. Based on the data, variables were registered on a daily basis and a random weekly check was conducted on the data against the medical records. Our Standard Operating Procedure was based on the following procedures: patient screening, selection and coding, sample collection, serum bank, DNA sample storage, monitoring systematization, surveillance systems to recover patients who had discontinued monitoring, etc.

In October 2011 the Base Data Monitoring Board for the last Interim Analysis, recommended an addendum modifying the secondary outcomes, adding simple and combined events. These events were characterized only by electrocardiographic abnormalities or associated to echocardiographic ones. These events were evaluated up April 2013.

Eligibility criteria: Inclusion Criteria:

* Patients living in urban areas
* Reactive to at least 2 for serological test performed in Fatala Chaben Institute (ELISA and IFI) ,
* Patients who agreed to be part of this protocol through informed consent form signed

Exclusion Criteria:

* Patients with chronic Chagas disease who have received prior treatment with benznidazole
* Other cardiomyopathies : idiopathic , alcoholic , peripartum myocarditis, secondary to coronary artery disease, valve disease, hypertension, restrictive, hypertrophic or congenital
* Chronic renal disease
* Bleeding disorders
* History of liver disease or current liver disease ,
* Any other severe clinical disease that decreases their life expectancy
* History of severe allergies
* Pregnant patients
* Patients who have not signed the informed consent.

Primary outcomes:
measure: Cardiovascular Mortality
timeFrame: Time to event: from date of randomization until the date of first documented progression or date of death from any cause up to 10 years of follow-up
measure: Development of heart failure
timeFrame: Time to event: from date of randomization until the date of first documented progression of heart failure up to 10 years of follow-up
measure: Severe arrhythmias with hemodynamic compromise or pacemaker implant or Implantable cardiac defibrillator
timeFrame: Time to event: from date of randomization until the date of first documented progression up to 10 years of follow-up
Secondary outcomes:
measure: Electrocardiographic endpoints. New development of permanent changes in the electrocardiographic
timeFrame: Time to event: from date of randomization until the date of first documented as defined in the secondary outcome up to 10 years of follow-up
measure: Changes in clinical stage in chronic Chagas disease
timeFrame: Time to event: from date of randomization until the date of first documented as defined in the secondary outcome up to 10 years of follow-up
measure: Enlargement of the left ventricle (LV) detected by echocardiography.
timeFrame: Time to event: from date of randomization until the date of first documented as defined in the secondary outcome up to 10 years of follow-up
measure: New Heart Failure
timeFrame: Time to event: from date of randomization until the date of first documented as defined in the secondary outcome up to 10 years of follow-up
measure: Stroke
timeFrame: Time to event: from date of randomization until the date of first documented as defined in the secondary outcome up to 10 years of follow-up
measure: Serological negativization
timeFrame: time to event: from the date of randomization to the date of the first documented serological negativization that persists until 10 years of follow-up
measure: Development and validation of RT-PCR
timeFrame: time to event: from the date of randomization to the date of the first documented no detectable RT-PCR that persists until 10 years of follow-up
measure: Changes of the secondary objectives during RCT development. New single endpoints
timeFrame: Since October 2011 during 18 months
measure: Combined clinical endpoints:
timeFrame: Since October 2011 during 18 months
Other outcomes:
Locations:
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: Instituto Nacional de Parasitología Dr Mario Fatala Chaben
state: Buenos Aires
Study officials:
affiliation: Chief of Clinical, Pathology and Treatment Department
name: Adellina R Riarte, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease. Am J Trop Med Hyg. 1998 Oct;59(4):526-9. doi: 10.4269/ajtmh.1998.59.526.
citation: 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.
citation: Viotti R, Vigliano C, Armenti H, Segura E. Treatment of chronic Chagas' disease with benznidazole: clinical and serologic evolution of patients with long-term follow-up. Am Heart J. 1994 Jan;127(1):151-62. doi: 10.1016/0002-8703(94)90521-5.
citation: Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez MG, Postan M, Armenti A. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann Intern Med. 2006 May 16;144(10):724-34. doi: 10.7326/0003-4819-144-10-200605160-00006.
citation: Porcel BM, Bontempi EJ, Henriksson J, Rydaker M, Aslund L, Segura EL, Pettersson U, Ruiz AM. Trypanosoma rangeli and Trypanosoma cruzi: molecular characterization of genes encoding putative calcium-binding proteins, highly conserved in trypanosomatids. Exp Parasitol. 1996 Dec;84(3):387-99. doi: 10.1006/expr.1996.0127.
citation: Kuschnir E, Sgammini H, Castro R, Evequoz C, Ledesma R, Brunetto J. [Evaluation of cardiac function by radioisotopic angiography, in patients with chronic Chagas cardiopathy]. Arq Bras Cardiol. 1985 Oct;45(4):249-56. No abstract available. Spanish.
citation: Reyes PA, Vallejo M. Trypanocidal drugs for late stage, symptomatic Chagas disease (Trypanosoma cruzi infection). Cochrane Database Syst Rev. 2005 Oct 19;(4):CD004102. doi: 10.1002/14651858.CD004102.pub2.
citation: Villar JC, Perez JG, Cortes OL, Riarte A, Pepper M, Marin-Neto JA, Guyatt GH. Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection. Cochrane Database Syst Rev. 2014 May 27;2014(5):CD003463. doi: 10.1002/14651858.CD003463.pub2.
citation: Schijman AG, Bisio M, Orellana L, Sued M, Duffy T, Mejia Jaramillo AM, Cura C, Auter F, Veron V, Qvarnstrom Y, Deborggraeve S, Hijar G, Zulantay I, Lucero RH, Velazquez E, Tellez T, Sanchez Leon Z, Galvao L, Nolder D, Monje Rumi M, Levi JE, Ramirez JD, Zorrilla P, Flores M, Jercic MI, Crisante G, Anez N, De Castro AM, Gonzalez CI, Acosta Viana K, Yachelini P, Torrico F, Robello C, Diosque P, Triana Chavez O, Aznar C, Russomando G, Buscher P, Assal A, Guhl F, Sosa Estani S, DaSilva A, Britto C, Luquetti A, Ladzins J. International study to evaluate PCR methods for detection of Trypanosoma cruzi DNA in blood samples from Chagas disease patients. PLoS Negl Trop Dis. 2011 Jan 11;5(1):e931. doi: 10.1371/journal.pntd.0000931.