Clinical trial NCT05519046: Cardiac Contractility Modulation in Chagas Heart Disease
Official title: Clinical and Functional Effects of Cardiac Contractility Modulation in Chagas Heart Disease: a Randomized Study - Contractility - FIX-Chagas
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Chagas Cardiomyopathy
Heart Failure
Systolic Dysfunction
Right Bundle Branch Block and Left Anterior Fascicular Block
Right Bundle Branch Block and Left Posterior Fascicular Block
Lead sponsor: InCor Heart Institute
Sponsor class: OTHER
Collaborators: name: Impulse Dynamics
name: I2medi Comercial Medica LTDA
First posted: 2022-08-29
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Chagas disease is an endemic problem in Latin America, where millions of people are chronically infected with T. cruzi. Recently, it was assumed to have clinical and epidemiological relevance in several other countries due to migratory and globalizing social factors. CCC occurs in 30-50% of infected individuals, causing considerable morbidity/mortality rates. Heart failure is the most prevalent morbidity. While CRT and drug treatment have been advocated and implemented without much success to improve the clinical condition of patients with CCC, there is no consistent scientific evidence on the role of cardiac contractility modulation (CCM) as a form of adjuvant treatment for heart failure in patients with CCC.

The hypothesis of this study is that patients with CCC, advanced heart failure, severe systolic dysfunction, and non-LBB have better clinical and functional responses when undergoing implantation of a CCM device than when undergoing cardiac resynchronization therapy.

Detailed description: Chagas Disease:

Chagas disease (Trypanosomiasis Americana) is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to humans through the feces of a hematophagous insect (family Triatominae) in most cases. The infection usually occurs in childhood, and the acute phase has an incubation period of 1 to 2 weeks and can last up to 3 months. Then follows the chronic phase, in which for a long time - 2-4 decades most of the time - patients have only positive serology for Chagas disease (CD), without symptoms or other signs of clinically apparent disease.

Therefore, such patients present the so-called indeterminate form of Chagas disease, whose prognosis is essentially benign.

While due to pathogenic mechanisms still incompletely understood, many patients remain with this form of the disease for life around 30 to 50% of infected individuals evolve to certain forms like cardiac, digestive, or mixed. Chronic Chagas cardiomyopathy (CCC) has a hemodynamic pattern like dilated idiopathic cardiomyopathy but has marked pathophysiological peculiarities. The most common and most serious clinical form of CD is responsible for significant morbidity and mortality in many Latin countries -Americans (and with epidemiological relevance also contemporarily recognized in countries with immigration by individuals from those countries).

It is estimated that 8-10 million people are infected with Trypanosoma cruzi in Latin America and other countries. Considering the worst-case scenario, we can deduce that 3-5 million infected individuals will manifest clinical forms of the disease in its chronic phase.

The disease severity:

In addition to the criteria used in the risk stratification shown in Tables 1 and 2, several markers of worse prognosis have been identified by several authors, especially concerning sudden cardiac death in different clinical contexts.

Characteristics such: as presyncope and syncope; left ventricular dysfunction; heart failure; sustained ventricular tachycardia (VT) or non-sustained ventricular tachycardia; severe bradyarrhythmia (sinus node disease and advanced atrioventricular block); and previous cardiac arrest were identified as markers of risk of sudden cardiac death (SCD). On the other hand, isolated ventricular extrasystoles on Holter monitoring and right bundle-branch block do not significantly interfere with the prognosis of CCC. SCD is often associated with manifestations of heart failure (HF), but it can also occur in patients with asymptomatic left ventricular dysfunction. It accounts for approximately 55 to 65% of all causes of death, whereas refractory HF is a cause of death in about 25 to 30% of patients and systemic or pulmonary thromboembolism in about 10 to 15%. Indicador não definido. Very rarely, aneurysm rupture can be the mechanism of sudden death in CCC.

Recently, the correlation between CCC stages and causes of mortality has been schematically described. SCD usually affects patients from stage II of the disease onwards, being more relevant in stage III and a little less in stage IV, in which refractory heart failure as a cause of death becomes quite frequent.

Therapeutic Options for Heart Failure. As in other heart diseases, the treatment of HF in CCC is based on the routine use of a combination of three types of drugs: diuretics, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARB) and adrenergic beta-blockers (BB). However, despite CD representing an important cause of HF in Latin America, patients with CD and HF were not included in the large studies that validated those drugs to treat HF. Therefore, the real efficacy and tolerability of these drugs in patients with CCC have not been scientifically established, and their use is empirically extrapolated from the support obtained in HF of other etiologies.

In the same sense, the scientific evidence regarding the role of CRT in CCC is not supported by randomized studies. Furthermore, the low prevalence of left bundle block, an independent marker of CRT response, in CCC is a limiting factor for its indication of this therapeutic option. Some observational studies have been carried out to recognize other candidates for CRT in CCC, but the evidence is still poor.

Heart transplantation is a good option for severe cases, but its application is very limited by the low availability of donors.

Recently, an excellent adjunctive option was introduced, and tested in several heart diseases but not in patients with CCC. It is an implantable device capable of modulating myocardial contractility: Cardiac Contractility Modulation (CCM).

Cardiac Contractility Modulation:

CCM consists of high-tension stimulation of the right ventricular septum during the absolute refractory period, 30-40ms after cardiomyocyte activation. This stimulation acts on calcium currents and increases ventricular contractility and, as a consequence, improves functional capacity.

In a 2019 meta-analytic study, Mando R et al. evaluated four randomized studies that applied the CCM technique compared to optimized drug therapy. The authors concluded that, in short-term follow-up, there is health-related quality of life gains (as measured by the Minnesota questionnaire) and that these were significantly greater in patients treated with CCM. However, they did not observe significantly better results in the functional test evaluated by the 6-minute walk test, nor regarding mortality and hospitalization from any causes.

Abraham WT et al. performed an open-label randomized trial to evaluate the adjunctive effect of CCM therapy to optimized therapy in 160 patients with symptoms of HF functional class III or IV by NYHA classification, sinus rhythm, QRS duration \<130ms, and LVEF ≥25%, and ≤45%. Of these, 74 patients underwent CCM therapy for 24 weeks. The results indicated that CCM therapy is safe and improves exercise tolerance and quality of life. The composite endpoint of cardiovascular death and HF hospitalizations was also reduced and clinical effects were observed for the entire LVEF range studied. More specifically, superior clinical efficacy was observed in patients with LVEF between 35% and 45%. These data point in the direction that CCM may be an interesting adjuvant option in HF therapy.

Hypothesis:

The hypothesis of this study is that patients with CCC, advanced heart failure, severe systolic dysfunction, and non-LBB have better clinical and functional responses when undergoing implantation of a CCM device than when undergoing cardiac resynchronization therapy.

Objectives:

Primary objective - To assess the short-term impact on quality of life and myocardial contractility of an implantable electronic cardiac device for cardiac contractility modulation compared to CRT in patients with CCC, non-LBBB, and advanced HF.

Secondary objectives - To record the clinical evolution, including the need for hospitalization, the functional class according to the New York Heart Association, and the functional capacity of an implantable electronic cardiac device for cardiac contractility modulation compared to CRT, in patients with CCC, non-LBBB, and advanced HF.

Eligibility criteria: Inclusion Criteria:

* Signing of an informed consent form (ICF) before randomization and any study procedure,
* Both genders, age \>18 years and \<75 years,
* Recent positive (last two years) and documented serology for Chagas disease, in at least two different tests (indirect hemagglutination, indirect immunofluorescence, or ELISA),
* NYHA II-III heart failure functional class,
* LVEF\< 35%,
* Non left bundle branch block
* Intraventricular desynchrony (Yu index)
* Global longitudinal strain \>11 %.

Exclusion Criteria:

* Participation in another study, presently or terminated \<1 year ago, except for a totally unrelated observational study,
* Other concomitant cardiovascular diseases, including uncontrolled diabetes mellitus (systemic arterial hypertension without permitted target organ compromise),
* Kidney dysfunction (serum creatinine \>1.5mg/dL or eGFR \<30mL/min/1.73m2) or liver dysfunction, with diagnosis of cirrhosis or portal hypertension or elevated serum enzymes (AST or ALT) \> 3x the upper limit of normality,
* Moderate or severe chronic obstructive pulmonary disease,
* Peripheral polyneuropathy,
* Hyperthyroidism,
* Current alcoholism or not abandoned for \>2 years,
* Diagnosed with psychopathy or psychosis or addiction to illicit drugs,
* Life expectancy \<1 year, due to the disease itself or comorbidities (including NYHA class IV),
* Pregnancy or breastfeeding,
* Potential to become pregnant during the study (non-menopausal patients who have not undergone a radical and safe contraceptive process),
* Previously withdrawn from this study.

Primary outcomes:
measure: QoL Score
timeFrame: At baseline
measure: QoL Score
timeFrame: At 6 months
measure: GLS
timeFrame: At baseline
measure: GLS
timeFrame: At 6 months
Secondary outcomes:
measure: 6MWT
timeFrame: At baseline
measure: 6MWT
timeFrame: At 6 months
measure: NYHAFC
timeFrame: At baseline
measure: NYHAFC
timeFrame: At 6 months
measure: LVEF
timeFrame: At baseline
measure: LVEF
timeFrame: At 6 months
measure: Heart Failure Hospitalization (HFH) checklist
timeFrame: Through study completion, an average of 6 months
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: InCor - HCFMUSP
state: Sao Paulo
Study officials:
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