Condition or disease | Intervention/treatment | Phase |
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Atrial Fibrillation | Procedure: Catheter ablation Combination Product: Risk Factor Modification | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 120 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Intervention Model Description: | Patient will be randomized into catheter ablation arm or risk factor modification arm |
Masking: | None (Open Label) |
Masking Description: | prospective, randomized, open - label study |
Primary Purpose: | Treatment |
Official Title: | Catheter Ablation vs. Risk Factor Modification. A Randomized Study |
Estimated Study Start Date : | May 1, 2021 |
Estimated Primary Completion Date : | December 30, 2023 |
Estimated Study Completion Date : | December 30, 2023 |
Arm | Intervention/treatment |
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Active Comparator: Catheter ablation
Patients will undergo catheter ablation of atrial fibrillation.
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Procedure: Catheter ablation
Pulmonary vein isolation, or additional left or righ atrial lession.
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Experimental: Risk factor modification
Patiemt will undergo risk factor intervention (dietary intervention, physical intervention, alcohol reduction or abstinence)
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Combination Product: Risk Factor Modification
dietary restriction, physical exercise, reduced alcohol intake
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Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria (all three must be met):
Exclusion Criteria:
Czechia | |
Cardiocenter, 3rd Medical School, Charles University and University Hospital Kralovske Vinohrady | |
Prague, Czechia, 10034 |
Tracking Information | |||||
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First Submitted Date ICMJE | June 28, 2019 | ||||
First Posted Date ICMJE | July 9, 2019 | ||||
Last Update Posted Date | February 3, 2021 | ||||
Estimated Study Start Date ICMJE | May 1, 2021 | ||||
Estimated Primary Completion Date | December 30, 2023 (Final data collection date for primary outcome measure) | ||||
Current Primary Outcome Measures ICMJE |
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Original Primary Outcome Measures ICMJE |
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Change History | |||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE | Same as current | ||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||
Descriptive Information | |||||
Brief Title ICMJE | Catheter Ablation vs. Risk Factor Modification. | ||||
Official Title ICMJE | Catheter Ablation vs. Risk Factor Modification. A Randomized Study | ||||
Brief Summary | Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a prevalence of 2% in general population. Incidence and prevalence of AF has been slightly increasing due to increasing age, improved ability to treat cardiac diseases, and higher incidence of obesity and other risk factors associated with AF. AF is associated with higher morbidity and mortality mainly caused by heart failure and stroke. Catheter ablation (with pulmonary vein isolation as a cornerstone) presents the most effective treatment method of AF. Recent observational studies have shown that intensive risk factor and lifestyle modifications, such as weight loss, reduced alcohol intake, and increased physical activity, are also associated with improved rhythm outocome. Head-to-head comparison of this very different methods has not been done yet. The aim of the project is to compare the effect of catheter ablation with lifestyle modification (risk factor modification) in a prospective, randomized, multicenter study on the maintenance of sinus rhythm (monitored using implantable ECG reveal), and on the progression of the fibrosis of the left ventricle. | ||||
Detailed Description |
GOALS OF THE PROJECT The aim of our study is to compare the effect of catheter ablation of atrial fibrillation with risk factor modification strategy in a randomized study. The main hypothesis is that strict risk factor modification (weight loss, physical exercise improvement, and alcohol absence) in patients with AF will be associated with similar rhythm outcomes as catheter ablation. Beside the AF-recurrence and AF-burden as the primary endpoint, the co-primary endpoint will be the change in diffuse myocardial fibrosis and left ventricular mass, as assessed by cardiac MRI. JUSTIFICATION OF THE PROJECT As mentioned above, the estimated prevalence of AF is approx. 2% in general population, i.e. about 200,000 patients only in the Czech Republic. Moreover, the incidence of AF has been increasing. Despite wide use of catheter ablation of AF, such huge number of patients could not be handled by the current capacity of electrophysiological cath - labs in any country. The searching for other, alternative approaches in treatment of AF is warranted. This approach has been already validated in previous, aforementioned trials+ however, these trials enrolled either patients either after or before catheter ablation, and so far, no head-to-head randomized study comparing this two treatment strategies has been done. If the risk factor modification management has been proven to have similar efficacy as catheter ablation, many motivated patients could be treated using this simple, non-invasive approach. METHODS The study is planned as prospective, multicenter, randomized, non-inferiority trial comparing two different approaches in the treatment of AF. Symptomatic AF patients indicated for rhythm control strategy (i.e. restoriation and maintenance of SR) will be enrolled and randomized to catheter ablation or risk factor modification. Study population - inclusion criteria (all of three have to be met for enrollment) (i) symptomatic AF (paroxysmal, persistent, or long-standing persistent), and (ii) BMI ≥ 25, and (iii) signed informed content Study population - exclusion criteria:
BASELINE DIAGNOSTIC EXAMINATION Anthropometric measurement and the assessment of physical fitness - functional fiagnostics After informed content has been given, and before the randomization, all patients will undergo baseline anthropometric measurements (the height, weight, percentage of body fat, and waist-to-hip ratio measurement) and baseline evaluation of physical fitness (functional diagnostic). Additionally, blood will be drawn for biochemistry and cytokine analysis and baseline cardiac magnetic resonance (CMR) will be done. All patients will be asked to complete specific questionnaires for quality of life (QoL) assessment, and all patients will be implanted with an implantable ECG loop recorder (ILR). Functional diagnostics will be performed in all patients to assess the cardiorespiratory fitness, ventilatory parameters at rest and exercise. In the risk factor modification group, functional diagnostics will also be used to reveal any contraindication for physical training. Based on the results of functional diagnostics, an individualized and optimized physical training program will be prepared. An initial exercise spiroergometry test Vita Maxima with 12-lead ECG monitoring, blood pressure monitoring, and ventilation monitoring using exhaled air analysis will be carried out within one month of enrollment. The protocol will consist of a 3-min warm-up period (0.5 W/kg), followed by a ramp test with exercise intensity increased by 0.2 W/kg/min in women and 0.3 W/kg/min in men up to the maximal subjective tolerance. Criteria of test termination will be physical intolerance, inability to maintain ergometer rotation speed (in a range of 60-100/min), significant ECG changes, occurrence of significant cardiac arrhythmias, and an unacceptable increase in blood pressure. Based on the results of spiroergometry, the heart rate for mild and moderate aerobic exercise will be determined, as well as the maximum heart rate that could be even achieved (i.e., 85% of maximum heart rate). Cardiac magnetic resonance (CMR) CMR will be done using 1.5 Tesla scanners located at each of the three participating centers. Before CMR evaluation, the ventricular rate will be optimized with a target ventricular rate < 100/min. The evaluation of systolic function of both ventricles will be done using steady-state free precesion (SSFP) cine CMR sequences in long- and short axis, during breath-holds of 10-15 s with measurement of end-systolic and end-diastolic volumes, a calculation of the ejection fraction of both ventricles, and with a measurement of left ventricular myocardial mass. Parametric T1 mapping will be performed using shortened modified look-locker inversion recovery (ShMOLLI) breath-hold sequence in short axis to visualize and assess the diffuse myocardial fibrosis. This will be done natively and then after an i.v. injection of gadolinium contrast agent, which allows the calculation of the extracellular volume. Furthermore, standard late gadolinium enhancement imaging of regional myocardial fibrosis using inversion recovery T1-weightened sequences will be done. RANDOMIZATION Patients will be randomized to the catheter ablation group (CA) or risk factor modification group (RFM) in a 1:1 ratio; randomization will be done using randomization software. The software will be designed to account for BMI, and AF type, with the goal of having comparable groups regarding those characteristics. The randomization will be done in blocks of 10 patients. TREEATMENTS A. Catheter ablation arm Catheter ablation will be done within one month (maximum two months) of randomization. In patients with paroxysmal AF, PVI will also be performed. In patients with non-paroxysmal AF forms, additional lesion sets, except for PVI, will be allowed according to the guidelines of each participating center. The first three months following catheter ablation will be considered as a "blanking period," i.e., AF reoccurrences won´t be assessed as an endpoint. If AF reoccurs during this period, treatment using AADs or cardioversion will be allowed. During this period, AF episodes recorded on ILRs will not be calculated. Three months after ablation, AADs will be discontinued and ECG monitoring, using ILR, will be started, In case of a reoccurrence of symptomatic AF or atrial tachycardia (AT), re-do ablations, cardioversion, or AADs treatment during the follow-up period will be allowed, in accordance with the current guidelines and practice of participating centers. However, because the indication for any of them will be a reoccurrence of AF or AT, it will be assessed as the primary endpoint (i.e., AF reoccurrence). B. Risk factor modification arm The risk factor management intervention will be started after fulfillment of all the baseline diagnostic and functional examinations (spiroergometry, anthropometrical measurement, CMR) within one month after the enrollment of the patient. The aim will be a 10% weight loss over 6 - 12 months, an increase in physical fitness, and alcohol (optimally absolute, if possible) abstinence. To achieve weight loss goal, standard recommendations according to the standards of the national and international professional societies will be used, in particular, societies on obesitology and cardiology. The approach will be highly individualized. In general, low-caloric dietary menu will be used based on current recommendations in combination with low or moderate physical activity, based on the individualization principle. Aerobic exercise will initially be prescribed for 20 minutes per week gradually increasing to 200 min/week until the end of the study. The physical activity part of the intervention will be performed using different activities: gym-based exercise in small groups with a physician, individual exercise with remote activity monitoring, outpatient follow-up consultation with regular education, and assessment of achieved results. Based on the results of functional diagnostics, changes in individual heart rate for mild and moderate intensity training will be assessed. Nutritional intervention: intensive consultations with nutritional specialists will be done during the first three months after enrollment. The flow-chart of the on-line and personal consultation within the first three months is shown in the Table 1. A low-caloric dietary menu will be suggested and optimized by a nutritional specialist for each patient on individual basis respecting the comorbidities of the particular patient and planned increase in physical activity. Regular consultation with dietary specialists (on personal basis, or by phone) are planned for all patients also after three months, with less frequent intensity. The physical intervention will consist of three types of activities. i)regular gym-based training in small groups of approx. 5 patients, or individual training with trainer. Initially, training will be performed three times a week as circuit training to increase physical condition, muscle balance stabilization, and education of proper functional respiration (respiratory training). ii)Individual aerobic training: fast walking or Nordic walking: The intensity and frequency will be set individually based on initial spiroergometry, 1-2 training weekly in the beginning of the study with further increase. iii)Home-based training: 20 min physical exercise sets including functional respiratory training to increase respiratory capacity, and balance exercise to balance muscle disproportions. The physical intervention will be based on regular mild and moderate intensity aerobic exercise that will be gradually increased from 60 min/week up to 200 min/week and then continued until the end of the study. Patients will be taught how to use their optimal heart rate for aerobic exercise, and also warned about exceeding their maximum possible heart rate (i.e., not exceeding 85% of the maximum heart rate). All the aforementioned physical interventions will be continued through the end of the study period. The type and ratio of the aforementioned physical exercises will be changed over the study period. In the first three months, there will be more emphasis on regular gym-based training in small groups, and less emphasis on individual exercise. The goal will be to teach patients how to properly perform all the exercises as well as assisting patients in getting used to regular exercise. By the end of the third month, when the majority of patients should be used to perform regular physical activity, the ratio of types of physical activities will change a greater emphasis on individual physical activity and less emphasis on gym-based programs, done in groups. Since it is known that the adherence of patients to regular activity is affected by activity monitoring, all patients will have an opportunity to be monitored using remote activity monitoring (fitness bands) with a freely available smartphone application. Patient will be encouraged to use the fitness bands for the whole study period to monitor the habitual activity (steps/hour units) to document the increase of the activity in the risk factor modification arm since the randomization. Moreover, all physical activities could be stored at the web-page www.casprozdravi (energy income, weight, physical activities). This web-based tool allows the on-line discussion with therapeutic and will be free for all participants. Similarly, as in the catheter ablation group, the first three months will be assessed as a "blanking period" regarding the rhythm measurement It means, no rhythm assessment will be done and AF reoccurrences will not count as an endpoint. The use of AADs will be allowed during this period. In patients in sustained AF at the end of three months, electrical cardioversion will be recommended. Also, as in the catheter ablation group, AADs will be withdrawn at the end of the "blanking period," and the ECG monitoring using ILR will be started. Any AF reoccurrence after the "blanking period" will be assessed as endpoints (AF recurrence). Electrical cardioversion, AAD re-initiation, or catheter ablation will be allowed during the follow-up period, based on clinical judgment, patient symptoms, and current recommendations according to the guidelines. However, because these treatment modalities are indicated only in patients with AF, all of them could be done only in endpoint (i.e. AF recurrence) appearance. Moreover, the recommendation, especially for catheter ablation, will be that they are postponed so that the effect of the risk factor modification strategy can be fully pronounced. OUTPATIENT FOLLOW-UP After the end of the blanking period, follow-up visits will be scheduled at 3, 6, 9, and 12 months during the first year, and then every 6 months afterward. The follow-up protocol and ECG monitoring are the same in both arms. Routine 12-lead ECGs will be recorded at follow-up visit along with a physical examination of the patient, and a medical history update. At the 12-month follow-up, CMR, blood drawing, antropometric measurement, and physical diagnostics will be done. During this visit, patients will also be asked to complete follow-up QoL questionnaires. The anthropometric measurement will be done finally at the last visit of each patient, at the end of the 3rd year of the study. ENDPOINT MONITORING Any symptomatic or asymptomatic episode of AF or regular AT lasting > 30 sec will be considered as an arrhythmia reoccurrence. AF-free survival will be defined as a complete absence of any AF or AT during the follow-up period. The AF burden will be calculated as the percentage of time spent in AF or AT. All ECG endpoint will be analyzed using ILR recordings. All recordings from patients ILRs will be sent by home monitoring equipment, and analyzed by the core lab using commercially available software supplied by the monitoring equipment manufacturer. The core lab will consist from two experienced biomedical engineers and cardiologists. ENDPOINTS Primary endpoints:
Secondary endpoints
Power calculation and statistical analysis According to the present data, about 60-70% efficacy could be expected in the catheter ablation arm, and 50-60% in the lifestyle modification arm. Assuming the power of 80%, with alfa value of 5%, and non-inferiority margin 10%, 60 patients have to be randomized to each arm. For data description, standard descriptive statistical methods will be used: absolute and relative frequencies for categorical data and the median with 5-95% percentiles for continuous data. For categorical variables, statistical analysis was done using the chi-square or the Fisher exact test; for continuous variables, the Student t-test or Mann-Whitney U test will be used. Kaplan-Meier curves will be calculated for visualizing the occurrence of endpoints during follow-up. The influence of patient characteristics on the occurrence of endpoints will be calculated using logistic regression and the Cox proportional risk model, as appropriate. Statistical analyses will be done using SPSS v. 22.0 software (IBM Corporation, 2013). Randomization process and data management Randomization software will be developed by the team of statisticians and computer specialists of the Institute of Biostatistics and Analyses (IBA). The randomization software will respect the risk characteristics of patients, the randomization software will be designed to account for age, BMI, AF type, and LA size, with the goal of having comparable groups regarding those characteristics. The randomization will be done in blocks of ten patients. IBA presents the institution with the largest experience in biomedical statistics and data management in the Czech Republic, and has been participating in several similar studies. The randomization process will be done outside all participating centers using web-based randomization software, and therefore it will be independent of study subjects and site personnel. The website will be used not only for collection of baseline data and randomization, but also for collection of all outpatient follow-up data during the whole follow-up. IBA will be also responsible for data management during the whole study period. Each participating center will have an access to a dedicated part of the web page. The local investigator at each site will be responsible for data completeness and validity. The first interim analysis will be done after enrollment of the first 50 of patients, the next on annual basis. The final analysis will be done when the last enrolled patient will achieve 6 months follow-up. All regulations regarding medical confidentiality and data protection will be fulfilled. Safety monitoring The local investigators will be responsible for reporting of all adverse and serious adverse events to the local and multicenter ethical committee. Serious adverse event (SAE) will be defined as life-threatening events resulting in death or hospitalization. A Data Safety Monitoring Board will be constituted before the onset of the trial. All the interim analyses will be reported to the DSMB by the principal investigator on the annual basis. DSMB may suggest termination of the study at any time based on appearance of SAEs, or if one treatment approach is shown to be significantly superior than other during the interim analysis, using statistical criteria for acceptable deviations from the null hypothesis. DISCUSSION In the last 5 years, lifestyle modification has been shown to be a very promising treatment modality for AF. AF is the most common sustained cardiac arrhythmia with an estimated worldwide prevalence of about 33.5 million people. According to recent epidemiological studies, its prevalence may triple by 2050. Even if catheter ablations were associated with a 100% success rate, it would be impossible to treat the current or projected numbers using catheter ablation. So will lifestyle modification studies may seem to offer a panacea, those studies suffer from significant limitations and possible biases. For example, the most important and most extensive studies were both non-randomized, and all patients had either a history of catheter ablation (ARREST-AF), or were without a history of catheter ablation, but catheter ablation was allowed without limitations, based on the judgment of the attending physician during the follow-up period (LEGACY). A randomized study that directly compares catheter ablation with lifestyle modification strategy has not yet been done. Only a randomized study can really answer the question, how effective is lifestyle modification compared to catheter ablation. Additionally, a randomized study has to potential to indicate which patients would be most likely to benefit from a non-invasive treatment, thus increasing the number of successfully treated AF patients, without the use of invasive methods. Due to increasing incidence and prevalence of AF, the searching for other, alternative approaches in treatment of AF is warranted. If the risk factor modification management has been proven to have similar efficacy as catheter ablation, many motivated patients could be treated using this simple, non-invasive approach. |
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Study Type ICMJE | Interventional | ||||
Study Phase ICMJE | Phase 3 | ||||
Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Patient will be randomized into catheter ablation arm or risk factor modification arm Masking: None (Open Label)Masking Description: prospective, randomized, open - label study Primary Purpose: Treatment
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Condition ICMJE | Atrial Fibrillation | ||||
Intervention ICMJE |
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Study Arms ICMJE |
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Publications * | Not Provided | ||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||
Recruitment Status ICMJE | Not yet recruiting | ||||
Estimated Enrollment ICMJE |
120 | ||||
Original Estimated Enrollment ICMJE | Same as current | ||||
Estimated Study Completion Date ICMJE | December 30, 2023 | ||||
Estimated Primary Completion Date | December 30, 2023 (Final data collection date for primary outcome measure) | ||||
Eligibility Criteria ICMJE |
Inclusion Criteria (all three must be met):
Exclusion Criteria:
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years to 75 Years (Adult, Older Adult) | ||||
Accepts Healthy Volunteers ICMJE | No | ||||
Contacts ICMJE | |||||
Listed Location Countries ICMJE | Czechia | ||||
Removed Location Countries | |||||
Administrative Information | |||||
NCT Number ICMJE | NCT04011800 | ||||
Other Study ID Numbers ICMJE | CA-RFM | ||||
Has Data Monitoring Committee | Yes | ||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Responsible Party | Pavel Osmancik, Charles University, Czech Republic | ||||
Study Sponsor ICMJE | Charles University, Czech Republic | ||||
Collaborators ICMJE |
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Investigators ICMJE | Not Provided | ||||
PRS Account | Charles University, Czech Republic | ||||
Verification Date | January 2021 | ||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |