Etiologic Treatment With Benznidazole in Adult Patients With Chronic Chagas Disease. A Randomized Clinical Trial (TRAENA)
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|ClinicalTrials.gov Identifier: NCT02386358|
Recruitment Status : Completed
First Posted : March 11, 2015
Last Update Posted : March 11, 2015
The purpose of this study is:
-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).
- -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)
- -to develop the real-time polymerase chain-reaction (RT-PCR) to quantify the parasite load as an early therapeutic effect.
- to determine the potential of such serological and parasitological methods as predictors of therapeutic effect or failure.
|Condition or disease||Intervention/treatment||Phase|
|Chagas Disease||Drug: Benznidazole Drug: Placebo||Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||910 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Etiologic Treatment With Benznidazole in Adult Patients With Chronic Chagas Disease. A Randomized Double Blind Clinical Trial|
|Study Start Date :||March 1999|
|Actual Primary Completion Date :||December 2012|
|Actual Study Completion Date :||April 2013|
Active Comparator: Benznidazole
Benznidazole pills of 100 mg, dose 5 mg/Kg/day, twice a day during 60 days
Benznidazole at a dose 5 mg/Kg/day until 60 days have been completed or development of non-acceptable toxicity-
Other Name: Radanil (Roche Laboratory)
Placebo Comparator: Placebo
Placebo pills 100 mg, dose 5mg/Kg/day, twice a day, during 60 days
Placebo at a dose 5 m/Kg/day until 60 days
Other Name: Placebo pills
- Cardiovascular Mortality [ Time Frame: 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 ]Sudden death, unexpectedly in time and in its presentation,preceded by the abrupt loss of consciousness within a maximum of one hour of the onset of symptoms,when it happened during sleep or unexpectedly in a patient was stable until then. Related Death, when presented in a patient with signs of progressive heart failure.Ischemic or Hemorrhagic Stroke
- Development of heart failure [ Time Frame: Time to event: from date of randomization until the date of first documented progression of heart failure up to 10 years of follow-up ]Dyspnea is evaluated according to the classification of the New York Heart Association (NYHA),gallop rhythm, jugular venous distension, crackles in the lungs, edema or pleural effusion,hepatomegaly
- Severe arrhythmias with hemodynamic compromise or pacemaker implant or Implantable cardiac defibrillator [ Time Frame: Time to event: from date of randomization until the date of first documented progression up to 10 years of follow-up ]Sustained ventricular tachycardia, atrioventricular block, trifascicular block, Atrial fibrillation
- Electrocardiographic endpoints. New development of permanent changes in the electrocardiographic [ Time Frame: 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 ]
- Stable sinus bradycardia (<50 beats / min)
- Auriculoventricular blocks of 2nd and 3rd degree
- Left anterior hemi-block
- Complete right bundle branch block
- Atrial flutter or fibrillation
- Sustained ventricular tachycardia
- Changes in clinical stage in chronic Chagas disease [ Time Frame: 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 ]Clinical progression
- Enlargement of the left ventricle (LV) detected by echocardiography. [ Time Frame: 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 ]Clinical Progression
- New Heart Failure [ Time Frame: 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 ]Clinical Progression
- Stroke [ Time Frame: 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 ]Clinical progression
- Serological negativization [ Time Frame: 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 ]by ELISA F29 vs. conventional serology as a late indicator of efficacy or therapeutic failure.
- Development and validation of RT-PCR [ Time Frame: 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 ]Demonstration of RT-PCR as an early indicator of efficacy or therapeutic failure.
- Changes of the secondary objectives during RCT development. New single endpoints [ Time Frame: Since October 2011 during 18 months ]
- Any change in clinical stage 0 to II due to left ventricular enlargement demonstrated by echocardiogram, or I to III stage due to development of heart failure.
Complete left branch block
- 3. Atrial fibrillation
- 4. Repetitive ventricular extrasystoles: doublets, triplets, bigemina, trigeminus, ventricular tachycardia
- Combined clinical endpoints: [ Time Frame: Since October 2011 during 18 months ]
- Right bundle branch block associated with left anterior hemi-block.
- Parietal motility disorders of left ventricle by echocardiography (akinesia, hypokinesia, and dyskinesia) associated with impaired left ventricular systolic function.
- Parietal motility disorders of left ventricle by echocardiogram (Akinesia, Hypokinesia, dyskinesia) and /or impaired LV systolic function associated with new electrocardiographic changes (complete left branch block, right bundle branch block, left anterior hemi-block, ventricular extrasystoles.
- Occurrence of left ventricle aneurysm point by echocardiogram associated to ventricular arrhythmia (section 18.104.22.168.).
- Occurrence of left ventricle aneurysm point by echocardiogram associated with depression of LV systolic function by echocardiography.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02386358
|Instituto Nacional de Parasitología Dr Mario Fatala Chaben|
|Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina, 1063|
|Principal Investigator:||Adellina R Riarte, MD||Chief of Clinical, Pathology and Treatment Department|