A Trial Testing Amiodarone in Chagas Cardiomiopathy (ATTACH)

A Trial Testing Amiodarone in Chagas Cardiomyopathy (ATTACH)

Purpose:

The ATTACH trial, as currently designed, will primarily test whether a treatment with Amiodarone for at least 6 months has a trypanocidal effect among individuals with mild-to-moderate Chronic Chagas Cardiomyopathy. A secondary goal will be to confirm, in this population, a clinical benefit from this treatment (in terms of reducing mortality or cardiac arrhythmic events), and to explore whether a potential trypanocidal effect is associated with a clinical benefit.

Study Overview

• Status: Unknown
• Conditions: Chagas Cardiomyopathy
• Intervention / Treatment: Drug: Amiodarone Hydrochloride; Drug: Placebo Oral Tablet

Detailed Description

Investigators currently plan to enroll over 200 participants in Bogotá and Bucaramanga, Colombia. Such sample size will provide 82% of statistical power to detect at least a 30% relative reduction in the primary outcome. This is assuming that at least 75% of untreated participants will test positive at least once after three qualitative PCR assays for Trypanosoma cruzi during the 6th month after randomization (allowing for up to 10% losses to follow up and treatment adherence over 90%).

ATTACH is currently seeking collaborating centers internationally. The current funding structure will allow to test study hypothesis on trypanocidal effect, whereas data on clinical effects will be exploratory. Investigators expect to increase the sample size to at least 600 participants in order to a) enhance geographical variability/generalizability for the primary results and b) to achieve enough statistical power to test the hypothesis on clinical impact.

New centers are welcome to join this protocol, either as a placebo-controlled or as a pragmatic, open label trial. These centers will be working with the central coordination with their own funding/logistic capabilities. In the open label protocol, eligible, consenting participants will be randomly prescribed or not to Amiodarone. As assessing clinical impact will be the priority, new centers are not required to have on-site PCR capabilities. These centers are encouraged to store blood samples for PCR testing elsewhere later, if possible.

See details on eligibility, interventions and outcome measures below

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Juan C Villar, MD, MSc, PhD; Phone Number: 73200 16672727; Email: jvillarc@cardioinfantil.org
• Study Contact Backup: Name: Eliana Vaquiro, RN, CCRN; Phone Number: 73200 16672727; Email: evaquiro@cardioinfantil.org

Study Locations

• Colombia
  • Bogotá, Colombia
    • Recruiting
    • Fundacion Cardioinfantil - Instituto De Cardiologia
    • Contact: Eliana Vaquiro, RN, CCRN; Phone Number: 73200 6672727; Email: evaquiro@cardioinfantil.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

ATTACH will enroll individuals with positive serology for Trypanozoma cruzi and evidence of both structrural and rythm/conduction cardiac abnormalities, as defined by any of the following inclusion criteria

1. Structural cardiac abnormality (at least one):

   • NTpro-BNP values >125 ng/ml, or BNP values > 50 ng/ml
   • Left ventricular ejection fraction (LVEF) <50% or left diastolic diameter > 5.5 cm
   • Symptoms of heart failure, or one episode of acute heart failure over the last 12 months

2. Rrythm/conduction cardiac abnormality (at least one)

   • EKG monitoring showing 10 or more VPBs/hour or ventricular Tachycardia
   • EKG showing left anterior hemiblockade or right bundle branch blocakde
   • Use of a cardiac stimulation device as treatment for A-V block or Sinus node dysfunction

The protocol allows concurrent treatments for the condition (e.g. beta-blockers, ACE inhibitors, etc.) other than Amiodarone. Individuals meeting the above eligibility criteria who have previously received trypanocidal therapy (e.g. Benznidazole or Nifurtimox) can still be included, as long as they prove to be PCR positive for T. cruzi at enrollment. Co-intervention with these agents during the study will also be allowed, as per physician's judgment, either as open label treatment, or as part of another study not involving Amiodarone.

Exclusion criteria:

• LVEF < 30% or NYHA Class III-IV
• Medical prescription with chronic use of Amiodarone
• Pregancy (currently, or planned in the following 2 years), or childbearing age without reliable birth control
• Heart rate < 50 or AV blockade without treatment with cardiac stimulation device
• Contraindication for Amiodarone as per treating physician (e.g. because of long QT syndrome, thyroid disease, interstitial lung disease)
• Atrial fibrillation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amiodarone Hydrochloride; Oral treatment for at least 6 months	Drug: Amiodarone Hydrochloride; Starting (loading) dose 400 mg PO once a day for 10 days. Maintainance dose 200 mg PO once a day for at least 6 months, up to 24 months
Placebo Comparator: Placebo; Oral treatment for at least 6 months	Drug: Placebo Oral Tablet; Matching placebo for tablets of 200 mg of Amiodarone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive PCR for Trypanosoma cruzi	Conventional (qualitative) Polymerase Chain Reaction. At least one positive result out of three tests at least one week apart from each other	6 months after starting treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of clinical events	a) All-cause deaths; b) EKG-supported ventricular tachycardia or, c) Hospitalization for cardiac causes	Up to study closure or 24 months after randomization (whichever comes first)
Elements of the composite outcome of clinical events individually		Up to study closure or 24 months after randomization (whichever comes first)

Collaborators and Investigators

• Sponsor: Fundación Cardioinfantil Instituto de Cardiología
• Collaborators: Instituto de Corazón de Bucaramanga
• Investigators: Principal Investigator: Juan C Villar, MD, MSc, PhD, Department of Research, Fundación Cardioinfantil - Instituto de Cardiología; Principal Investigator: Diego A Rodriguez, MD, Department of Cardiology, Fundación Cardioinfantil - Instituto de Cardiología

Publications and helpful links

General Publications

• Rassi A Jr, Rassi A, Little WC, Xavier SS, Rassi SG, Rassi AG, Rassi GG, Hasslocher-Moreno A, Sousa AS, Scanavacca MI. Development and validation of a risk score for predicting death in Chagas' heart disease. N Engl J Med. 2006 Aug 24;355(8):799-808. doi: 10.1056/NEJMoa053241.
• Rassi A Jr, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas disease: a systematic review of observational studies. Circulation. 2007 Mar 6;115(9):1101-8. doi: 10.1161/CIRCULATIONAHA.106.627265.
• Veiga-Santos P, Barrias ES, Santos JF, de Barros Moreira TL, de Carvalho TM, Urbina JA, de Souza W. Effects of amiodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi. Int J Antimicrob Agents. 2012 Jul;40(1):61-71. doi: 10.1016/j.ijantimicag.2012.03.009. Epub 2012 May 14.
• Adesse D, Azzam EM, Meirelles Mde N, Urbina JA, Garzoni LR. Amiodarone inhibits Trypanosoma cruzi infection and promotes cardiac cell recovery with gap junction and cytoskeleton reassembly in vitro. Antimicrob Agents Chemother. 2011 Jan;55(1):203-10. doi: 10.1128/AAC.01129-10. Epub 2010 Nov 15.
• Benaim G, Sanders JM, Garcia-Marchan Y, Colina C, Lira R, Caldera AR, Payares G, Sanoja C, Burgos JM, Leon-Rossell A, Concepcion JL, Schijman AG, Levin M, Oldfield E, Urbina JA. Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole. J Med Chem. 2006 Feb 9;49(3):892-9. doi: 10.1021/jm050691f.

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2017
• Primary Completion (Anticipated): June 1, 2020
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: June 19, 2017
• First Submitted That Met QC Criteria: June 20, 2017
• First Posted (Actual): June 21, 2017

Study Record Updates

• Last Update Posted (Actual): June 21, 2017
• Last Update Submitted That Met QC Criteria: June 20, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Chagas disease, cardiomyopathy, amiodarone, clinical trial
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Chagas Disease; Trypanosomiasis; Euglenozoa Infections; Cardiomyopathies; Chagas Cardiomyopathy; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Enzyme Inhibitors; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Potassium Channel Blockers; Amiodarone
• Other Study ID Numbers: 880-2015; 277872553480 (Other Grant/Funding Number: Colciencias)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Upon submission of primary results, following requests of editors, by request to the steering committee

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No