Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT02347111 |
| Other study ID # |
2018-1299 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
December 31, 2020 |
| Est. completion date |
June 30, 2025 |
Study information
| Verified date |
November 2023 |
| Source |
University of Illinois at Chicago |
| Contact |
Dawood Darbar, M.D. |
| Phone |
6158879032 |
| Email |
darbar[@]uic.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In this pilot and feasibility study, the investigators will enroll patients with frequent
symptomatic episodes of atrial fibrillation (AF) in a cross-over study testing two different
classes of anti arrhythmic drugs (AADs). This pilot and feasibility study will provide
preliminary data for a larger study in which the investigators will test the hypothesis that
a common AF genetic risk allele modulates response to different AADs.
Description:
1.0 Background
While atrial fibrillation (AF) is the most common sustained cardiac arrhythmia requiring
therapy, it is also associated with increased risk of stroke, heart failure, myocardial
infarction, dementia, and death. The number of Americans affected with AF is expected to
surge to nearly 16 million by the year 2050. The AF epidemic may in part be related to the
aging of the population and increasing prevalence of recently identified risk factors
including obesity, metabolic syndrome, obstructive sleep apnea, and inflammation.
Furthermore, there is increasing support for the idea that both common and rare genetic
variants also increase susceptibility to AF which can clinically manifest in the presence of
acquired risk factors. While clinical risk factors for AF are established, the genetic
components of this "multiple-hit" genetic model for the development of AF have only recently
been identified.
Despite recent advances in catheter-based and surgical therapies, anti-arrhythmic drugs
(AADs) remain the mainstay of treatment for patients with symptomatic AF. However, response
in an individual is highly variable with more than half of patients treated with AADs
suffering a recurrence of AF within 6 to 12 months. The limited success of therapy for AF is
related to poor understanding of the underlying pathophysiology, heterogeneity of the
electrical and structural substrate, and the lack of targeted mechanism-based therapies.
Thus, one major knowledge gap is predicting response to AADs in an individual patient.
Contemporary membrane-active drugs used to suppress AF are incompletely and unpredictably
effective and are associated with significant risks of proarrhythmia and non-cardiac
toxicities. Furthermore, the current 'one-size fits all' approach to selecting AAD therapy
for a patient with symptomatic AF is based largely on minimizing the risk of adverse events
rather than on the likelihood of efficacy. Recent advances in our understanding of genetic
mechanisms of AF support the overarching hypothesis we wish to test in future studies that
variability in response to AAD therapy is modulated by common genetic variants associated
with AF. Several AF susceptibility loci have been identified and validated in genome-wide
association studies. In addition, we have shown that common AF risk single nucleotide
polymorphisms (SNPs) at the chromosome (chr) 4q25 locus not only predict poor response to
AADs but also recurrence of AF after ablation therapy and cardioversion.
While genetic approaches to AF have revealed that susceptibility to AF and response to
therapy are modulated in part by the underlying genetic substrate, the translation of these
discoveries to the bedside management of AF patients has thus far been limited. This relates
to poor understanding of the underlying mechanisms associated with common AF risk alleles,
challenges associated with determining efficacy of AADs and lack of genotype-directed
prospective studies. Our preliminary data showed that a common chr4q25 SNP associated with AF
predicted successful symptom control in patients treated with AADs and individuals who
carried the risk variant responded better to Vaughan Williams class I vs. class III AADs.
Based on the information collected in this feasibility and pilot study, we propose to conduct
a prospective pharmacogenomic study where a cohort of patients with frequent symptomatic
paroxysmal AF will be randomized to a flecainide (class I AAD) or sotalol (class III AAD) in
order to determine if response to therapy is modified by chr4q25 SNPs using AF burden as a
metric of drug efficacy. This main study, like the pilot study proposed here, will utilize a
crossover design to minimize inter-individual variability and maximize statistical power to
detect an interaction between chr4q25 genotype and the reduction of AF burden with flecainide
vs. sotalol. After a run-in period during which the AAD will be up-titrated, subjects will be
monitored with the Medtronic Reveal LINQ Insertable Cardiac Monitor (ICM) system to assess AF
burden. Furthermore, subjects will be asked to complete a comprehensive, validated 20-item AF
specific questionnaire (AF Effect on QualiTy-of-life [AFEQT]) at baseline, and monthly
thereafter for the duration of the study. At the end of the 6-month trial period, the AAD
will be discontinued and participants will be switched to the other AAD and followed for
another 6-month period in a crossover trial design.
2.0 Rationale and Specific Aims
We and others have shown common SNPs at the chr4q25 locus are associated with increased risk
of AF and modulate symptomatic response to AADs. Furthermore, our preliminary data suggests
that there is a differential response to class I vs. class III membrane-active drugs. Here,
we propose a pilot study to obtain preliminary data regarding AF burden in patients receiving
AADs and to demonstrate feasibility for a future study to test the hypothesis that chr4q25
risk SNPs modulate differential response to AADs in patients with frequent symptomatic
paroxysmal AF using reduction in mean AF burden as a metric of drug efficacy. Therefore, the
Specific Aim of this pilot/feasibility study is to obtain preliminary data regarding AF
burden in patients receiving AADs and to demonstrate feasibility for a future study to test
the hypothesis that chr4q25 SNPs modulate differential response to class I vs. class III AADs
in patients with frequent symptomatic AF.
3.0 Previous Human Studies
Chr4q25 SNPs modulate differential response to AADs in patients with AF In a preliminary
study we addressed whether symptomatic response to AAD therapy is modulated by the 3 common
AF susceptibility loci on chr4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3). We
studied 478 (discovery cohort) and 198 (validation cohort) age and gender matched Caucasian
patients in the Vanderbilt AF Registry. Response to AAD therapy was defined as successful
rhythm control if the patient remained on the same AAD therapy for a minimum of 6 months with
≥ 75% reduction in AF symptoms. Multiple clinical variables (including age, hypertension,
lone AF) failed to predict response to AADs. However, a SNP at the 4q25 locus (rs10033464)
was significantly associated with successful symptom control (odds ratio [OR] 2.97, 95%
confidence interval [CI] 1.42-6.21, P=0.003). Furthermore, individuals who carried the 4q25
SNP responded better to class I vs. class III AADs in both the discovery and validation
cohorts. These preliminary findings provide the rationale for our future studies by
suggesting that common AF susceptibility variants differentially modify the response to class
I vs. class III AADs in patients with frequent symptomatic AF.
4.0 Enrollment/Randomization
Patients ≥18 years of age with symptomatic paroxysmal AF will be enrolled from the Arrhythmia
and Cardiology Clinics, the Adult Emergency Department, and inpatient Cardiology services at
University of Illinois Medical Center. For patients with whom researchers do not have a
relationship, introductions from a member of their care team will be sought prior to
discussion of the study. After obtaining the permission of the patient, a member of the study
team will explain the study, answer any questions, and allow sufficient time to be certain
that the subject understands the study and has given their consent to participate. Consent
will be documented by signing the informed consent document, a copy of which will be given to
the subject.
5.0 Study Procedures
Randomization: Patients will be consented and randomized to either flecainide or sotalol for
six months and then crossed-over to the alternate drug for six months, regardless of the
efficacy of the first drug. Study randomization will be through http://www.randomize.net/.
Each participating will have access to the randomization application and each site
responsible per their local IRB regulations to maintain the randomization study list. The
study will be open-label.
Baseline visit procedures: The baseline visit will take place at the AF and Cardiology Clinic
at the Outpatient Care Center (OCC) of UIHHSS. This visit will involve reviewing eligibility
and the consenting process. Patients will present to the OCC and be met by a study physician,
who will perform a history and physical exam. A baseline 12-lead ECG will be obtained for all
patients and interpreted by the study physician to verify eligibility. Patients who meet the
criteria will be randomized into one of the two study medications (sotalol or flecainide),
and scheduled by a study nurse to come back to UIHHSS within one week to receive the
Medtronic Reveal ICM implantation and administered the initial dose of study drug.
For patients randomized to start sotalol first, they will be scheduled by the study nurse to
return to UIH in approximately 1 week to be admitted for up to 72 hours, which is routinely
done for sotalol administration. The designated cardiology/AF nurse will schedule this
admission after the consenting/baseline visit is completed in the clinic. At the second
visit, once inclusion and exclusion criteria are confirmed again for continued eligibility, a
peripheral intravenous catheter will be placed, and blood will be drawn for a basic metabolic
panel (BMP), particularly potassium (K+) and creatinine (Cr). This is routinely done for
patients hospitalized for initiation of sotalol. The study physician will determine the
initial sotalol dose (80 - 120mg twice a day by mouth) based on Cr CL.
Two hours after the first dose of study drug is given a 12-lead ECG will be recorded and
interpreted by the study physician. If the QTc is >500 msec, the sotalol dose will be reduced
under the direction of the study physician. Patients will be admitted for continuous
telemetric monitoring and will remain in UIH until the 5th dose is administered as long as
the physician confirms eligibility with each dose. Additional 12-lead ECGs will be obtained
two hours after the 3rd and 5th doses of sotalol to assess QTc duration. The BMP will also be
drawn to routinely monitor the subject's K+ and Cr. If the QTc duration remains >500 msec
even after adjustment of the sotalol dose, the drug will be stopped and the patient will be
excluded from the study. If the QTc remains ≤500 msec after the 5th dose of sotalol, the
patient will be discharged to home. A phone call will be made by the study coordinator or
study physician 3 days after discharge to check subject's status and ensure they are
tolerating sotalol and are not experiencing any untoward side effects.
Patients randomized to flecainide at the baseline visit will initially be scheduled for
follow up at the UIH Electrophysiology Laboratory within one week. At the second visit, once
inclusion and exclusion criteria are confirmed again for continued eligibility, a LINQ ICM
will be inserted. The patient will be observed for two hours after the ICM insertion. During
this time, an ECG will be performed and a quality of life (QoL) questionnaire will be
administered. After 2 hours of observation after ICM insertion, the 1st dose of flecainide
will be administered (50-100mg at physician's discretion). As per guidelines for flecainide,
subjects will also concomitantly be started on either beta blockers (25 mg by mouth once a
day) or diltiazem (120 mg long-acting by mouth once a day) based on the patient's
tolerability. An AV nodal blocker like beta blockers and diltiazem is often co-prescribed
with flecainide to prevent the development of 1:1 conducted atrial flutter.
After the 1st dose of flecainide (+beta blockers /diltiazem), there will be 2 hours of
observation to capture any outcomes/adverse reactions, and another ECG will be done to
examine the PR interval and QRS duration. The study physician will review these and decide if
patient is eligible to continue and make any adjustments as needed. A 3-day phone call will
be made by the study physician or another member of the research team to check subject's
status and obtain any outcomes.
End of study procedures: Patients will be scheduled for a clinic visit with their primary
cardiac arrhythmia physician to coincide with the termination of the study (12 months). A
study physician will also be available to conduct a brief patient interview, pill count, and
ICM interrogation. All pertinent clinical data including AF burden on each AAD, maximal
tolerated dose, and any reported side effects will be given to the primary arrhythmia
physician to aide in clinical decision making about future AAD
Early study termination, early crossover, and procedures to treat persistent AF: Based on our
prior clinical experience, a proportion of patients (20 to 30%) are expected to experience
residual symptomatic episodes of AF while taking either or both study AADs. Usually these
episodes will be less bothersome or lengthy. Patients will be encouraged to continue the
study protocol if possible. However, a smaller proportion of patients might have intolerable
symptoms necessitating an unscheduled change in therapy. The study team will work with the
primary cardiac electrophysiologist to facilitate any necessary change in therapy. An early
crossover to the alternative study AAD will be encouraged over a change to a non-study AAD
when possible. A change in therapy to a non-study AAD or AF ablation procedure will be
allowed when necessary. In addition, if patients acquire persistent AF during the course of
the study, electrical cardioversion will be allowed and will be coordinated by the study team
and the primary cardiac electrophysiologist. AF burden data for patients deviating from the
study protocol will be analyzed using an "on treatment" analysis. In other words, the AF
burden will be calculated per day that patients are on each study AAD. Patients will also be
allowed to withdraw from the study for personal or other reasons at any time. Patients are
volunteering their time, so they reserve the right to withdraw from the study at any point.
Insertable cardiac monitor management after study termination: At the conclusion of the
twelve-month study, patients will be given the option to remove or retain the ICM. We
anticipate that most patients and their primary arrhythmia physicians will opt to retain the
device to allow for continued cardiac monitoring, which is not only useful to gauge response
to AAD therapy but also frequently used to monitor AF recurrence for patients undergoing
catheter ablation. If the ICM is retained, its management, including removal, will be
transferred to the primary electrophysiologist. Patients wishing to have the ICM removed at
the end of the study period will be scheduled for an outpatient visit to the UIH EP
Laboratory for removal by a study physician.
Primary end point and its determination: The primary endpoint will be mean AF burden over six
months as measured by the Medtronic Reveal LINQ ICM system. All patients are scheduled to
remain in the study for 12 months. The FDA-approved Medtronic Reveal LINQ ICM system is able
to continuously monitor the heart through a single-lead ECG and has a specific algorithm that
detects AF by evaluating the irregularity of R-R intervals.The device is able to correctly
classify AF in 96.1% of patients and correctly exclude AF in 97.4% of subjects.The device is
able to monitor the heart for up to 3 years and is compatible with the Medtronic CareLink
Network remote monitoring system. This system allows the treating physician to download
device and diagnostic data through a secure network. Patients transmit data manually after
the device indicates that one of the alert criteria have been met. The occurrence of symptoms
with the AF episode will be recorded, but both asymptomatic and symptomatic AF will be
included in the primary endpoint measurement of AF burden.
For the primary analysis, AF burden will begin to be tabulated after an initial run in period
for each study drug. For patients starting sotalol, the run-in period will coincide with the
first 5 doses (60 hours). For patients starting flecainide, the run-in period will last until
a dose of at least 200 mg per day (in divided doses) is achieved, unless a smaller dose is
the maximally tolerated dose. Ideally, this will be achieved within 3-4 days after initiation
of flecainide. If, during the course of the study, a patient develops persistent AF, a
cardioversion will be scheduled in coordination with the patient's primary
electrophysiologist. The patient will then be switched to the other study drug. In case of
such an occurrence, AF burden will be tabulated using an "on treatment" analysis. Conditions
for which a patient will be withdrawn from the study and data censored will be
discontinuation of AAD therapy, initiation of amiodarone, AF ablation or AV node
ablation/permanent pacing, loss to follow-up, elective withdrawal from the study, or death.
Blood processing, DNA extraction, and genotyping: Blood samples will be drawn into
ethylenediamenetetraacetic acid (EDTA) tubes and immediately refrigerated at 4° C. Plasma
will be separated by centrifugation and stored at -80° C. DNA will be extracted from the
buffy coat using a commercially available kit (Qiagen Puregene, Valencia, California) and
stored at -20° C. Study participants will be genotyped for three common chr4q25 SNPs
(rs2200733, rs17570669, and rs3853445) using Sanger sequencing.
6.0 Risks
Risks will be minimized by performing study procedures in the UIHHSS EP Laboratory. A
complete history and physical examination will be performed to ensure that subjects fulfill
the entry criteria as defined. All identifying documents and data collected as a result of
this study will be retained by the investigator. Data will be entered into the secure
Research Electronic Data Capture (REDCap) database. Access to this material will be available
only to the research investigator and his staff. If results of this study are to be
published, only randomized code numbers will be used for identification purposes.
Participants will not be identified by name.
Risks associated with the Medtronic Reveal LINQ ICM: Risks associated with insertion of the
ICM include pain and discomfort, bleeding, bruising, hematoma, infection, and an allergic
reaction to the skin prep or lidocaine used for local anesthesia. There is a very small risk
of long-term discomfort associated with having the device. According to the manufacturer, the
ICM is fully MRI-compatible immediately after implantation.
Risks associated with sotalol: Therapeutic doses of sotalol range from 160 mg to 240 mg per
day. Common side effects of sotalol therapy include bradycardia (13% to 16%), chest pain (3%
to 16%), palpitations (14%), fatigue (20%), dizziness (20%), lightheadedness (12%), weakness
(13%), dyspnea (21%), edema (8%), hypotension (6%), proarrhythmia (5%), syncope (5%), heart
failure (5%), torsade de pointes (dose related; 1% to 4%), peripheral vascular disorders
(3%), ventricular tachycardia worsened (1%), QTc interval prolongation (dose related),
headache (8%), sleep problems (8%), mental confusion (6%), anxiety (4%), depression (4%),
rash (5%), sexual side effects (3%), nausea/vomiting (10%), diarrhea (7%), stomach discomfort
(3% to 6%), flatulence (2%), impotence (2%), bleeding (2%), extremity pain (7%), paresthesia
(4%), back pain (3%), visual problems (5%), upper respiratory problems (5% to 8%), and asthma
(2%). Rare (<1%) side effects of therapeutic doses of sotalol include alopecia, bronchiolitis
obliterans with organized pneumonia (BOOP), cold extremities, diaphoresis, eosinophilia,
leukocytoclastic vasculitis, leukopenia, paralysis, phlebitis, photosensitivity reaction,
pruritus, pulmonary edema, Raynaud's phenomenon, red crusted skin, retroperitoneal fibrosis,
elevated liver transaminases, thrombocytopenia, and vertigo.
Risks associated with flecainide: Therapeutic doses of flecainide range from 200 mg to 300 mg
per day. Common side effects of flecainide therapy include dizziness (19% to 30%), visual
disturbances (16%), dyspnea (10%), palpitations (6%), chest pain (5%), edema (3.5%),
tachycardia (1% to 3%), proarrhythmia (4% to 12%), sinus node dysfunction (1.2%), syncope,
headache (4% to 10%), fatigue (8%), nervousness (5%), fever, malaise, hypoesthesia, paresis,
ataxia, vertigo, somnolence, tinnitus, anxiety, insomnia, depression, rash (1% to 3%), nausea
(9%), constipation (1%), abdominal pain (3%), anorexia (1% to 3%), diarrhea (0.7% to 3%),
tremor (5%), weakness (5%), paresthesia (1%), diplopia (1% to 3%), and blurred vision. Rare
(< 1%) side effects include alopecia, altered pacing threshold, amnesia, angina, AV block,
bradycardia, bronchospasm, heart failure, corneal deposits, depersonalization, euphoria,
exfoliative dermatitis, granulocytopenia, heart block, increased PR interval, leukopenia,
metallic taste, neuropathy, paradoxical increase in ventricular rate in atrial
fibrillation/flutter, paresthesia, photophobia, pneumonitis, pruritus, increased QRS
duration, swollen lips/tongue/mouth, tardive dyskinesia, thrombocytopenia, urinary retention,
urticaria, and ventricular arrhythmias.
Risks associated with oral beta blockers use: Therapeutic dose of beta blockers ranges from
50 mg to 200 mg per day. Common side effects of chronic beta blockers therapy include
tiredness (26%), dizziness (13%), depression (12%), cold, tingling, or numbness in the hands
or feet (12%), and shortness of breath (6%). Other common adverse effects of beta blockers
include slow heart rate (bradycardia), a decrease in blood pressure when going from a
lying-down or sitting position to standing, a spinning sensation (vertigo), lightheadedness,
diarrhea, and nausea. We will use a low dose of beta blockers (25 mg) in this study to
minimize the risk of occurrence of these adverse effects. Rare (< 1%) side effects of
therapeutic doses of beta blockers include an increase in liver enzymes, allergic reactions,
headache, impotence (also known as erectile dysfunction), Peyronie's disease, worsening of
psoriasis, reversible hair loss, vision problems, dry mouth, Raynaud's phenomenon,
unexplained rash, and dry eyes. These adverse effects are not anticipated with a single low
dose of beta blockers that will be administered to our volunteers. Beta blockers can rarely
cause an allergic reaction (<1%) that manifests as rash, itching, swelling, severe dizziness,
or trouble breathing. Any subject with a previous history of allergy or intolerance to
beta-blockers will be excluded from the study.
Risks associated with oral diltiazem use: The therapeutic dose of diltiazem ranges from 120
mg to 480 mg per day. Common side effects of chronic diltiazem therapy include edema (2% to
15%), headache (5% to 12%), AV block (first degree 2% to 8%), bradycardia (2% to 6%),
hypotension (2% to 4%), vasodilation (2% to 3%), extrasystoles (2%), flushing (1% to 2%),
palpitation (1% to 2%), dizziness (3% to 10%), nervousness (2%), rash (1% to 4%), gout (1% to
2%), dyspepsia (1% to 6%), constipation (<2% to 4%), vomiting (2%), diarrhea (1% to 2%),
weakness (1% to 4%), myalgia (2%), rhinitis (<2% to 10%), pharyngitis (2% to 6%), dyspnea (1%
to 6%), bronchitis (1% to 4%), cough (≤3), and sinus congestion (1% to 2%). Rare (< 1%) side
effects of diltiazem include an increase in alkaline phosphatase, allergic reaction, increase
in liver transaminases, amblyopia, amnesia, arrhythmia, AV block (second or third degree),
bundle branch block, heart failure, depression, dysgeusia, extrapyramidal symptoms, gingival
hyperplasia, hemolytic anemia, petechiae, photosensitivity, Stevens-Johnson syndrome,
syncope, tachycardia, thrombocytopenia, tremor, and toxic epidermal necrolysis.
Risks associated with venipuncture: Potential problems related to establishing an intravenous
access include pain, bleeding, hematoma, fainting, and rarely infection at the venipuncture
site.
7.0 Reporting of Adverse Events or Unanticipated Problems Involving Risk to Participants or
Others
All adverse events will be reported to the institutional review board (IRB) within five
business days as required by institutional policy. A serious adverse event is defined as an
untoward medical occurrence that results in death, is life-threatening, requires
hospitalization, results in persistent or significant disability, or requires intervention to
prevent permanent disability or death. Other untoward medical occurrences that do not meet
the above criteria will be classified as adverse events. Study personnel who are
administering the research protocol in the UIH EP Laboratory will monitor for adverse events,
with the assistance of the designated nursing staff. All suspected or confirmed adverse
events will promptly be reported to the PI, who will collect data on these occurrences. The
PI will report serious adverse events to the IRB within 5 days of being notified.
8.0 Study Withdrawal/Discontinuation
Participation in the study is strictly voluntary, and patients will be able to withdraw at
any time. Following the subject's withdrawal, any samples collected will be destroyed and not
analyzed further, although any analyzed data will be maintained.
9.0 Statistical Considerations
Sample size: The primary outcome will be comparison of mean reduction in AF burden when
treated with flecainide vs. sotalol for 6 months each. Based on our pilot study, the mean AF
burden on flecainide was 20±14% (SD). As the minor allele frequency (MAF) of rs10033464 is
~12%, the ratio of carriers to non-carriers is ~1:8. A mean reduction in AF burden of 10% in
chr4q25 AF risk allele vs. WT allele carriers may be clinically meaningful assuming that half
of the patients will receive flecainide first and the other half sotalol first. In order to
detect at least a 50% difference in AF burden on the two AADs (absolute difference of 10%),
the study requires a total of 162 patients to achieve 80% power in detecting the difference.
Sample size computation was performed using an approximate t-test with pooled variance
estimate that compared mean reduction in AF burden over 6 months with a 2-sided 5%
significance level. SD of the mean reduction in AF burden was estimated to be 14% (based on
the pilot study) assuming a correlation of 10% among repeated measures and a 20% drop-out
rate.
Statistical analysis: The primary study endpoint will be AF burden (the proportion of time a
patient is in AF) and will be calculated for each subject while being treated with flecainide
and sotalol. For the primary analysis, we will test the hypothesis that the chr4q25 AF risk
allele (rs10033464) modulates the treatment effect difference between flecainide and sotalol.
The average burden difference on the two treatments between patients carrying the AF risk
allele and those carrying the WT allele will be calculated and the hypothesis will be tested
using an approximate t-test based on the standardized score (divided by its standard error).
No adjustment of covariates such as age and gender will be required because the cross-over
design controls for such variables. The analysis will be performed both on the patients who
complete the study and on all patients intended to treat with outcomes of the drop-outs
imputed. Conventional imputations using last-observation-carry-forward, as well as
model-based imputations will be performed to assess the robustness of the findings based on
patients who complete the study.
A secondary analysis using a mixed effects model will be performed treating the AF burden
score measurement over the treatment course of a patient as longitudinal data. Clinical
covariates that may affect AF burden (age, male sex, diabetes mellitus, HTN, valvular
disease, coronary artery disease, heart failure, and obesity) will be included in the mixed
effects model to examine the effects of a patient's profile, AAD therapy, as well as their
interactions with the AF burden scores. [In addition, a number of exploratory analyses will
be performed on other AF risk alleles, particularly the other 3 most common chr4q25 AF SNPs
(rs2200733, rs17570669, rs3853445) associated with AF in EAs26 to determine if any of them
modulate response to flecainide and sotalol, using the same test for the primary analysis
based on the AF burden scores. Specifically, the analysis will explore (a) the joint effect
of all 4 AF SNPs using a multivariate test; (b) the effects of individual SNPs if the global
test detects statistical significance; and (c) the effect of collapsed genetic scores created
by coding each patient's genotype as the sum number of variant alleles carried across all 4
AF SNPs. We expect that the chr4q25 SNPs may demonstrate a sufficiently strong association
with AF burden to drive the effect observed in our combined analysis of all 4 SNPs. As is
common practice in genetic analysis of complex diseases like AF, all analyses will be tested
using both dominant and additive genetic models.
10.0 Privacy/Confidentiality Issues
All research hard copy records will be stored in a locked cabinet within a locked office with
access only to the research personnel. Digitalized ECG recordings will be de-identified and
stored in a password-protected electronic database. Only the investigators and members of the
study team will have access to the code key.
A possible risk of the research is that information about a patient's health might become
known to individuals outside the research. The investigators have put in place measures to
minimize this risk as described below.
All identifying documents, data, and specimens collected as a result of this study will be
retained by Dr. Darbar. Data will be entered by hand onto a blank copy of the data collection
packet, which was generated on the secure Research Electronic Data Capture (REDCap) database.
The more comprehensive study in the future will most likely use the REDCap database directly
online for convenience. Access to this material will be available only to the research
investigator and his staff. If results of this study are to be published, only randomized
code numbers will be used for identification purposes.
Completing the QoL questionnaires will not pose greater loss of confidentiality as all forms
will be kept with the subject file. These files will be safely stored in Dr. Darbar's
research offices, in a filing cabinet that is locked. Only the research staff and Dr. Darbar
have access to this locked cabinet. The information will only remain with the designated
research staff. If results of this study are to be published, only randomized code numbers of
subjects will be used to protect their identity. Participants will not be identified by name
or any study identifiers.
11.0 Follow-up and Record Retention
We expect that the study will span a period of 12 months. All data will be archived and
stored indefinitely.
