Download Registry Proposal - Pediatric and Congenital Electrophysiology

Intravenous Sotalol in Pediatric and Congenital Patients:
A Multi-center Registry
Background:
Though intravenous sotalol has been used outside the US for over thirty years, it was only
recently approved by the Food and Drug Administration (FDA; 2009) and reintroduced to the US market
(2015). Sotalol is a class III antiarrhythmic agent that prolongs action potential duration while also
blocking beta-adrenergic receptors. Intravenous (IV) sotalol has been used for many different types of
tachyarrhythmias with the distinct advantage of having an oral equivalent with more tolerable side effects.
This is of particular importance in pediatric patients as well as young adults with congenital heart disease
who will likely remain on antiarrhythmic therapy for long periods of time (potentially a lifetime).
Additionally, collateral damage to developing organ systems by other class III antiarrhythmics makes
sotalol an important alternative in this population.
Currently, IV sotalol is indicated for substitution of oral sotalol in patients who are unable to take
oral medications per the FDA. Infusion options are based on the current adult literature, FDA guidance,
and modeling with reported infusion times between one and thirty minutes, most commonly five
minutes1,2. Typical IV sotalol doses have been reported around 1-1.5mg/kg/dose3. However, pediatric
dosing for IV sotalol has not been well studied, with a single case series from Zhang4 et al using IV
sotalol in children with normal left ventricular function.
The purpose of this study is to evaluate the safety and efficacy of IV sotalol being given for
tachyarrhythmias to pediatric patients as well as adults with congenital heart disease. Our goal is to
collect approximately 100 patients from 10 centers over an 18 month time period. To facilitate this, a
multicenter prospective nonrandomized registry study will be performed to address specific aims.
Primary Aims:
Aim1. To study the safety of IV sotalol administration through monitoring of blood pressure, heart rate,
telemetry, and frequent electrocardiograms.
We hypothesize that IV sotalol can be safely used to terminate atrial, ventricular and junctional
tachyarrhythmias in the pediatric and congenital population. Administration of intravenous
antiarrhythmics typically occurs in an intensive care unit, where there is continuous assessment of patient
vital signs and rhythm. Collected data will include heart rate (HR) and blood pressure (BP) before and at
the end of treatment, as well as minimum and maximum values during infusion. Additionally,
electrocardiographic data, including QTc will be collected from enrolled patients. Safety markers will
include events of bradycardia, sinus arrest, severe hypotension during treatment, treatment related
arrhythmias, QTC prolongation >480ms, need for inotropic support or escalation of support during
treatment, and death.
Aim2. To evaluate the efficacy of IV sotalol by assessing tachycardia termination, reduction or ratecontrol.
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We hypothesize that IV sotalol will be highly efficacious in the termination, reduction or ratecontrol for pediatric and congenital tachyarrhythmias. Patients spanning the spectrum of
tachyarrhythmias—atrial, junctional, and ventricular—will be included in the registry. Efficacy will be
assessed by monitoring telemetry and ECGs with data input for rate and rhythm before, during, and after
infusions. Additionally, other potential patient effects that may occur will be noted. Efficacy markers
will include successful termination, time to termination, and recurrence.
Aim3. To report the clinically employed effective dose and rate of administration for IV sotalol.
We hypothesize that patient clinical status, coupled with clinical judgment will influence the dose
and rate of IV sotalol administration. Given that this is a registry study, there will not be a prescriptive
protocol for drug administration; rather, data collected will include the amount of drug administered
(calculated in mg/kg, mg/m2) and the rate of administration (over minutes-hours). For the purposes of
analysis, rates of administration will be binned as short (<1 hour), intermediate (1-4 hours) and long (≥5
hours). Data collected will include patient clinical status pre and post drug infusion.
Protocol:
Once eligible patients have been identified (please see below inclusion/exclusion criteria), participating
centers will complete an online data collection form. The primary site for online database creation,
management and administration will be West Virginia University. Data collected at participating sites
will be de-identified and uploaded to the system by either site PI or designee.
Demographic and clinical parameters obtained will include:
 Age, sex, height, weight
 Heart rate
 Blood pressure
 EKG parameters (PR, QRSd, QT, QTc)
 Echocardiogram parameters (Fractional shortening, EF, qualitative estimate)
 Arrhythmia Diagnosis (provide deidentified scanned EKG, 12 lead or rhythm strip for
investigator review)
 Arrhythmia type (paroxysmal, sustained, non-sustained, incessant, intermittent sustained,
intermittent non-sustained)
 Additional diagnoses
 Symptoms
 Prior anti-arrhythmia treatment (drug with outcome, ablation)
 Heart rate at initiation of treatment
 Arrhythmia duration prior to the initial of treatment
 Reason for IV sotalol use
 Dose of IV sotalol (total dose, dose per kg, dose per m2)
 Duration of infusion
 Hemodynamic data before, during and after administration
 Result of IV sotalol administration (arrhythmia outcome, time to termination, recurrence,
QTC/PR/HR maximum at the end of infusion, BP minimum at the end of infusion, need to slow
or terminate infusion early, symptoms post infusion, recurrence, time of recurrence)
 Patient outcome
 Follow up (single dose only, subsequent periodic administration vs. infusion, transition to oral
sotalol)
 Other effects reported
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Inclusion Criteria:
Patients who meet the following criteria will be eligible for participation in this study:
1. All ages included, with a subgroup analysis for adults with congenital heart disease. Pediatrics
considered newborn to age 18.
2. Patients with a tachyarrhythmia including; supraventricular tachycardia, atrial ectopy, atrial
tachycardia, atrial fibrillation, junctional ectopic tachycardia, ventricular ectopy, and ventricular
tachycardia.
Exclusion Criteria:
1. Patients that do not meet inclusion criteria as above will be excluded.
Safety Considerations Prior to Administration:
Since this a registry study on clinical use, there are no specific exclusion criteria, but the following
findings related to safety of administration should be considered prior to use.
1. LVEF <50% by echocardiogram prior to administration
2. Sinus bradycardia for age or condition, sick sinus syndrome or second and third degree AV block
unless functional pacing wires are present (either permanent or temporary)
3. Congenital or acquired long QT syndromes,
4. QTc (Bazett’s) > 450msec (in the presence of narrow complex QRS, or adjusted for the QRS
duration, consider JTc)
5. Decreased creatinine clearance <40mL/min (sotalol dose adjustments recommended)
6. Cardiogenic shock or decompensated heart failure
7. Bronchial asthma or related bronchospastic conditions
8. Known hypersensitivity to sotalol
Previously published data/recommendations for administration:
1. FDA Guidance
 5 hour infusion (based on similar bioavailability and pharmacokinetics to oral; no clinical studies)
2. Data in the literature supports the following
 Doses of 1-1.5 mg/kg, or 95% of an oral dose
 Bolus (acute administration in the cath lab with intensive monitoring)
 5 minutes (acute administration in the cath lab with intensive monitoring)
 10 minutes (Zhang et al)
 30 minutes (multiple studies)
 > 30 minutes
3. Modeling data (University of Maryland)
 2 hours provides nearly identical profile to oral in simulated data
 1.5 minutes yields similar maximum concentrations to 160 mg PO BID
 Loading protocols for IV/PO load
 40 mg over 2 hours followed immediately by 80 mg PO BID yields nearly equivalent
levels to the steady state reached after 72 hours after the first PO dose
 60 mg over 2 hours followed immediately by 120 mg PO BID yields nearly equivalent
levels to the steady state reached after 72 hours after the first PO dose (QTc can be
checked after 1 hr of 30 mg during the load to assure safety)
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
80 mg over 2 hours followed immediately by 160 mg PO BID yields nearly equivalent
levels to the steady state reached after 72 hours after the first PO dose (QTc can be
checked after 1 hr of 40 mg during the load to assure safety)
4. Monitoring
Data in the literature suggests that in postoperative adults, cardiac output decreases moderately due to a
reduction in heart rate. However, in other settings any reductions in blood pressure seem to be of minor
significance in most patients. In the only published pediatric study of IV sotalol, the drug was only
administered after an echocardiogram demonstrated an EF > 50%.
The following might be considered:
 Some prior knowledge of systemic ventricular function before administration
 In early postoperative patients, monitoring of arterial pressure with an indwelling catheter is
probably prudent
 Sotalol is a beta-blocker, so administration during concomitant administration of catecholamines
or inotropes should probably be done with caution.
 Frequent blood pressure monitoring is reasonable in all patients during any initial IV sotalol dose
 Frequent blood pressure monitoring is reasonable in all patients during any administration over
≤1 hour.
Data analyses:
We intend to use SAS software for statistical analysis. We will use mean values +/-standard error with
confidence intervals, and proportions with confidence intervals. To look at the difference in time to
termination compared to administration rate we will use wither Kaplan Meier curves and/or ANOVA
comparisons using a p value < 0.05 as significant.
Sample size: With a sample size of 100 patients we will have good precision for estimating the reported
safety concern, proportion of patients with QTc prolongation and the efficacy marker, proportion of
patients that terminated. For example if we found that 8% of the patients had QTc prolongation, the 95%
confidence interval for the proportion would be (2.7%, 13.3%) and if the proportion of patients that
terminated was found to be 69%, the 95% CI would be (59.9%, 78.1%).
Budget:
We propose that each participating site contract separately with AltaThera for reimbursement. Briefly,
each site will be compensated for IRB fees and receive a uniform “per patient” reimbursement from
AltaThera once data forms are completed. The WVU data center will ensure data forms have been
submitted and adequately completed. WVU will send a report to AltaThera each month specifying by
center which forms have been submitted in order for AltaThera to provide accurate center reimbursement.
The study steering committee will ultimately oversee the form completion reports to AltaThera.
Please see appendices for attached budget proposals.
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Participating Sites:
We propose initially including 5-6 sites. Using the list of hospitals that currently have the drug on
formulary (provided by AltaThera), the steering committee will contact institutions to gauge their interest
in participating in such a registry. Additionally, we used the Pediatric and Congenital EP Society
(PACES) pre-Heart Rhythm Society Scientific Sessions research meeting to propose the registry to the
pediatric community at large.
Additionally, we will re-forward an updated copy of the proposal to the PACES Research Committee for
their overview. Once approved, the registry would qualify as a PACES approved study.
Currently confirmed sites (with site PI):
Site
Washington University SOM/St Louis Children’s Hospital, MO
Children’s Mercy Hospital, Kansas City, MO
West Virginia University, Morgantown, WV
PI
Jennifer N. Avari Silva, MD
Lindsey Malloy-Walton, DO, MPH
J. Philip Saul, MD
Steering committee for this study is as follows:
Name
Jennifer N. Avari Silva, MD
Lindsey Malloy-Walton, DO,
MPH
J. Philip Saul, MD
Site
Washington University
School of Medicine, St
Louis, MO
Children’s Mercy
Hospital, UMKC,
Kansas City, MO
West Virginia
University,Morgantown,
WV
Title
Director, Pediatric EP
Assistant Professor,
Pediatrics
Assistant Professor,
Pediatrics
Executive Vice President,
Children’s Hospital
Professor , Pediatrics
Role
Protocol creation, patient
enrollment, data analysis,
manuscript preparation
Protocol creation, patient
enrollment, data analysis,
manuscript preparation
Protocol creation, patient
enrollment, data analysis,
manuscript preparation
Writing committee:
Participating sites will each designate a single site PI who will participate in the preparation of the
manuscript. Each site that enrolls at least one patient will be limited to 1 member on the writing
committee.
Timeframe:
Submission of proposal to AltaThera
Submission of proposal to PACES
Presentation of proposal @ pre-HRS PACES research meeting
Creation of online database
Creation of individual site IRBs
Submission of site specific budgets to AltaThera
Patient enrollment
Abstract submission to HRS 2018
Manuscript preparation
Manuscript publication
May 2016
March 2016
May 2016 – Done
May 2016 – July 2016
May 2016-October 2016
May2016-October 2016
June 2016-January 2018
December 2017
Spring 2018
Summer 2018
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References:
1. Ho DS, Zecchin RP, Cooper DA, Richards AB, Uther JB, and Ross L. Rapid intravenous
infusion of d-1 sotalol: time to onset of effect on ventricular refractoriness, and safety. European
Heart Journal 1995:16;81-86.
2. Sung R, Tan HL, Karagounis L, Hanyok J, Falk R, Platia E, Das G, Hardy SA and the Sotalol
Multicenter Study Group. Intravenous Sotalol for the Termination of Supraventricular
Tachycardia and Atrial Fibrillation/Flutter: A Multicenter Randomized, Double-Blind Placebo –
Controlled Study. American Heart Journal 1995:129;739-48.
3. Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callawa C, Kudenchuk PJ, Ornato JP,
McNally B, Silvers SM, Passman RS, White RD, Hess EP, Tang W, Davis D, Sinz E, and
Morrison LJ. AHA/ACC/HRS 2010 Guidelines for Cardiopulmonary Resuscitation and
Emergency Cardiovascular Care. Part 8: Adult Advanced Cardiovascular Life Support.
Circulation 2010:122l;S729-S767.
4. Zhang Y, Li X, Xu Z, Lui H. Efficacy of Intravenous Sotalol for treatment of incessant
tachyarrhythmias in Children. Chinese Journal of Practical Pediatrics 2013:28;4.
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