Right Ventricular Septal Pacing in Patients With Right Bundle Branch Block and Heart Failure, a Pilot Clinical Trial (The SPARK Trial)
Phase: NA
Conditions: Right Bundle-Branch Block, Heart Failure
Sponsor: Barry London

 
 
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Principal Investigator (PI):   
 
Barry London, MD 
 
 
 
 
 
 
 
 
 
 
Title of Study:  
Right Ventricular Septal Pacing in Patients with 
Right Bundle Branch Block and Heart Failure, a 
Pilot Clinical Trial 
 
Study Center:  
University of Iowa 
  
 
Estimated number of subjects:  
40 adults over the age of 18  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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I. 
Introduction ..................................................................................................................................... 3 
II. 
Background ..................................................................................................................................... 5 
III. 
Statement of Compliance................................................................................................................ 7 
IV. 
IRB Oversight .................................................................................................................................. 8 
V. 
Location of Study Procedures ........................................................................................................ 9 
VI. 
Main Hypothesis ............................................................................................................................ 10 
VII. 
Inclusion/Exclusion Criteria ........................................................................................................ 11 
VIII. Study Procedures .......................................................................................................................... 13 
IX. 
Adverse Event Reporting: ............................................................................................................ 14 
X. 
Data Management ......................................................................................................................... 17 
XI. 
Subject Safety ................................................................................................................................ 18 
XII. 
References ...................................................................................................................................... 19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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I. 
Introduction 
Heart failure is the fastest growing cardiovascular diagnosis in the United States, with a 
prevalence of approximately2.5% in adults. The direct and indirect costs of heart failure 
exceed $33 billion per year. 
Heart failure condition is commonly associated with abnormalities in the heart electrical 
conduction system that leads to losing the ability to achieve strong synchronized 
contractions. 
During last decade, Cardiac Resynchronization therapy (CRT) has evolved as one of the 
standard therapies in heart failure field to target this issue; many large randomized controlled 
trials showed that this therapy significantly improves symptoms, heart function, rate of 
hospitalization, and overall mortality. 
CRT requires pacemaker implantation in the cardiac catheterization laboratory. Implanted 
pacemaker activates or pace the heart in a synchronized fashion to minimize the deleterious 
consequences of the electrical abnormalities that are usually associated with heart failure. 
It is well known now that patients with a specific conduction disease called left bundle 
branch block (LBBB) represent the heart failure group that benefit the most from this 
therapy, while heart failure patients with right bundle branch block(RBBB), another 
conduction disease, who represent around 10% to 15% of heart failure patients do not 
benefits as much. 
CRT activates the areas of the heart that is affected mainly by LBBB not RBBB, it requires 
the addition of an extra leader wire to the regular defibrillator device that heart failure 
patients usually have, this procedure is usually done in the cardiac catheterization lab and 
considered as an invasive procedure. 
As most patients with moderate to severe heart failure including who have RBBB meet 
current guidelines recommendations for defibrillator placement to prevent sudden cardiac 
death, most of them have already a defibrillator that is capable of pacing too and is placed 
routinely in the area of the heart that can normalize the RBBB associated electrical 
abnormalities if it would be paced by an appropriately programmed device. 
In our proposed clinical trial, we are planning to recruit heart failure patients with only right 
bundle branch block who have already defibrillator or pacemaker, and after obtaining an 
informative consent, we will program their pacemaker/defibrillator to provide a novel form 
of CRT that target RBBB as we mentioned earlier without any need for an invasive 
procedure. 
Our study’s design is a randomized controlled single blinded cross-over study. Overall 
designs will include two 12 weeks treatment periods separated by 8 weeks washout periods. 

 
 
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One group will have pacing-washout-placebo sequence while the other will have placebo-
washout-pacing sequence. Subjects will be randomized to either pacing (intervention) ornon-
pacing (placebo) with 1:1 ratio at the initial visit. each subject will undergo heart ultrasound 
(echocardiogram), symptoms/quality of life assessment, and 6 minute walking distance 
assessment at initial, 12, 20, 32 weeks visits. This type of clinical trial design will have an 
advantage of blinding the intervention to the subject which will minimize bias and would 
create a control group. Indeed, will allow still to use relatively small number of subjects with 
enough power to test outcomes comparable to single arm prospective trial design, while 
parallel randomized controlled studies design would require higher subjects numbers for 
reaching an adequate power to test outcomes of interest due to lack of self control. 
This study will allow us to evaluate the effect of this intervention on heart failure symptoms, 
heart size and function as well as quality of life in this specific group of heart failure patients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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II. 
Background 
Several randomized trials and meta-analyses (1,2,3,9,10) conducted within the last decade showed 
that bi-ventricular cardiac resynchronization therapy (BIV-CRT) is an effective therapy for heart 
failure (HF) patients with LVEF=<35%and NYHA class III and IV symptoms who are on optimal 
medical therapy and have left bundle branch block (LBBB)with or without ICD. Most recently, some 
studies have shown that BIV-CRT benefits extend to HF patients that are less symptomatic [NYHA 
class I and II symptoms].(8,9) BIV-CRT significantly decreases all-cause mortality and 
cardiovascular morbidity including a reduction in heart failure hospitalizations, and it is associated 
with remarkable symptomatic improvement in HF patients at short term. Reverse positive remodeling 
represented by the decrease in left ventricular (LV) size, improvement of intra- and inter-ventricular 
synchrony and eventually improvement in LV function is the main mechanism of action of this 
therapy. 
Many studies showed that the presence of right bundle branch block (RBBB) in patients with 
cardiovascular disease is associated with worse cardiovascular outcomes (4). Overall, RBBB 
prevalence in HF population according to previous studies ranges from 10-15% (3,9). 
It is well known from previously conducted studies that BIV-CRT is most effective in patients with 
LBBB and that non-LBBB patients including RBBB patients tend to be overall non-responders with 
similar outcomes profile of the patients who underwent only ICD implantation(3,5,11). Studies have 
linked the response to CRT to the presence of the left intra-ventricular and/or inter-ventricular 
desynchrony which are common in LBBB patients(2,14). Indeed, patients who did show some 
response to BIV-CRT in the RBBB group were more likely to have left-sided dyssynchrony (6), left 
sided conduction disease (15), non-LAFB conduction pattern (5) or prolonged PR interval >230 ms 
(7). In the last scenario, the response was likely due to the correction of atrio-ventricular 
dysynchrony. 
RBBB is associated with wide QRS and often with wall motion abnormalities and inter-ventricular 
dyssynchrony. Right sided intra-ventricular dyssynchrony or conduction delay is common and 
significant which can be accompanied sometimes by also left sided dyssynchrony(6,14). If those 
abnormalities can be minimized by a specific right sided pacing therapy, it may potentially result in 
reverse right ventricular remodeling and secondary left ventricular remodeling interventricular 
interdependence phenomenon which may lead to an improvement in cardiac output and 
hemodynamics as BIV-CRT does in LBBB situation. 
RBBB patients have an intact conduction through the left bundle branch, thus pacing only the right 
ventricle targeting just the diseased right bundle branch and utilizing the normal conduction through 
left system may work better than pacing both ventricles together or only Left ventricle (14). By 
optimizing atrio-ventricular delay interval setting when programming the pacemaker/ICD, we can 
achieve a narrow fused ventricular activation wave (QRS complex) in RBBB patients that results 
from fusion of both the pacemaker wave and the normally conducted intrinsic wave through the intact 
left bundle branch. This may restore the normal ventricular activation sequence and hence we may 
achieve the wished effects described above. 

 
 
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Placement of the right ventricular (RV) lead tip varies in location between the RV apex and the mid 
portion of the septum. We do expect that mid septal location of RV lead (or sometimes called right 
ventricular outflow "RVOT" lead)would result in better fusion of ventricular activation waves 
(13)and thus will be likely more effective in restoration of the electrical and mechanical synchrony 
than apical RV leads. Apical lead not uncommonly creates iatrogenic LBBB that can be sometimes of 
deleterious effect on HF patients. Current practice has shifted toward septal lead placement, but apical 
leads are still common. Our study will include both types of RV lead location and will hopefully add 
some insight into this. 
We are currently publishing interesting data which shows that right ventricular pacing in RBBB 
patients by mid septal leads can significantly reduce QRS duration and achieve narrow fused QRS 
waves(12). Also, we are working on case series to report the effect of this pacing intervention on 
normalizing wall motion abnormalities associated with RBBB by echocardiogram. 
We believe that this is an attractive pacing therapy for heart failure that is worthy of further study; we 
hypothesize that Cat by only a single RV lead in HF patients with RBBB and has LVEF=<35% 
would improve heart failure symptoms by inducing reverse remodeling process and likely have a 
significant impact on cardiovascular outcomes, hopefully similar to those seen with BIV-CRT in HF 
patients with LBBB. 
Our proposed study will be the first on this topic, as no published clinical trials can be found in the 
literature using this technique of CRT therapy. We expect that if we can prove that such intervention 
leads to positive remodeling and HF symptom improvement that would create interest in proceeding 
with a large multi-center randomized clinical trial to test this therapy’s effect on major cardiovascular 
outcomes which may lead to major changes in the current guidelines of the pacing therapies in heart 
failure. 
Tens to hundreds of thousands of heart failure patients in the United States who are not candidates for 
current conventional BIV-CRT due to the presence of RBBB, already have a right ventricular lead as 
part of their defibrillator implanted for sudden cardiac death prevention and may benefit from such 
intervention if we find it is effective. Our proposed intervention requires only a simple re-
programming of their device' in other means we would provide potentially an added therapy to be 
delivered by devices that have already been implanted for another indications. Known current BIV-
CRT therapy is associated with significant survival gain. Later studies have quantified this gain by 
analyzing multiple landmark CRT trials; Finegold JA el et as an example found that the number needs 
to treat (NNT) to save one life is 15 at 3 years in RAFT trial, which represents a breakthrough in 
medicine. This huge survival benefit that requires only low number of patients to be treated to save 
lives makes us excited to proceed with our proposed trial. 
 
 
 
 

 
 
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III. 
Statement of Compliance 
This study will be conducted in compliance with the protocol, Good Clinical Practice and the 
applicable Food and Drug Administration and other Department of Health and Human 
Services regulatory requirements. 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection and Good Clinical Practice training. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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IV. 
IRB Oversight 
 
Human Subjects Office / IRB 
J. Andrew Bertolatus, MD 
Hardin Library, Office 105 
600 Newton Rd 
Iowa City, IA 52242 
FWA#: FWA00003007 
Voice: 319-335-6564 
Fax: 319-335-7310 
Email: irb@uiowa.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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V. 
Location of Study Procedures 
 
University of Iowa  
200 Hawkins Drive 
Iowa City, Iowa 52242 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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VI. 
Main Hypothesis 
To determine whether cardiac resynchronization therapy by single right ventricular lead in 
heart failure patient with RBBB will be associated with positive reverse left ventricular 
remodeling and improvement in heart failure symptoms and quality of life. 
Primary endpoint Positive reverse left ventricular remodeling, defined as increase in LV 
Ejection Fraction >15% from baseline at 6 months. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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VII. 
Inclusion Criteria 
 
Our subject population is one group of patients who has the diagnosis of systolic heart 
failure. 
Inclusion criteria: 
Cardiomyopathy, ischemic or non-ischemic on optimal medical therapy per 
current heart failure treatment guidelines for at least 3 months. 
LVEF <=35% by echocardiogram 
Prior implantation of pacemaker/defibrillator with at least atrial and RV mid 
septal leads. Atrial lead can be waived if RV lead has atrial sensing capabilities. 
Presence of right bundle branch block (RBBB), with QRS duration =>120 msec 
Normal sinus rhythm 
PR interval <250 msec on surface EKG 
-Note: Subjects with Biventricular pacemaker/ICD will be enrolled if their LV lead 
has been deactivated by the their primary cardiologist prior to study enrollment for at 
least 3 months (this could be due to lead malfunction or the decision to deactivate the 
biventricular pacing therapy for any reason per primary cardiologist discretion) 
 
Exclusion Criteria 
 
Age younger than 18 years old 
 
Any other known conditions other than heart failure that could limit survival to < 
6 months. 
 
Acute Myocardial infarction within 6 months of entry into the study 
 
Pregnancy 
 
Inotrope dependent heart failure condition 
 

 
 
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Left ventricular assist device (LVAD) or heart transplantation 
 
Atrial fibrillation or flutter burden >10% within the last 6 months 
 
Atrioventricular node block disease requires ventricular pacemaker support >10% 
of the time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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VIII. Study Procedures  
 
After informative consent signed by potential subject and at the same visit (initial 
visit), every subject will undergo pacemaker/defibrillator screening check, 
transthoracic echocardiogram if no echocardiogram available within 6 months 
preceding the initial visit, and pregnancy test for females whose age 18-50 year-old, if 
subject is deemed still eligible based on the results of this initial visit screening tests, 
he/she will be randomized to one of the study's arm and undergo the following 
baseline tests/procedures. 
 
Initial visit baseline tests/procedures: 
 
A- 6-minute walking test if subject has not had one within 3 months prior to 
enrollment. 
B- Subject will be requested to fill two questionnaires: 
1- “Minnesota living with heart failure” questionnaire to assess your quality of life 
2- “Self-assigned New York Heart Association survey (SA-NYHA)” to evaluate the 
severity of your heart failure symptoms. 
C- Medications review, vital signs (heart rate, blood pressure measurement, and 
weight) 
D Baseline pre- and post-programming 12 leads EKG 
E- Pacemaker/defibrillator programming session will be performed on all subjects. 
Patient assigned to the arm that start with pacing initial treatment period, their devices 
will be programmed according to our study protocol for RBBB pacing therapy. 
 
After the initial visit, subject will be scheduled for follow up visits. Each visit will 
last approximately (60-120 minutes) and will be located at University of Iowa Heart 
and Vascular center –adult outpatient facilities where each subject will have the 
following tests performed: 
 
A-Follow up trans-thoracic echocardiogram 
B-Follow up 6-minute walking test 
C-Subject will be requested to fill the two-questionnaire mentioned above again for 
follow up purposes. 
D-Medications review, follow up vital signs (heart rate, blood pressure measurement, 
and weight) 
E-Subject will be asked whether has been hospitalized, has had any medication 
changes, or has suffered any acute myocardial infarction or stroke/TIA for the 
preceding 3 months. 
F- Blood draw for laboratory tests (Sodium, BUN, Cr, and NT-proBNP) 
G-Baseline pre- and post-programming 12 leads EKG 
H-Follow up pacemaker/defibrillator check 
 

 
 
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IX. 
Adverse Event Reporting: 
 
The University of Iowa requires Investigators to collect and report to the University of Iowa 
IRB if any of the following occur: 
 
• An unanticipated problem involving risks to subjects or others is any event or 
problem that: 
1) was unexpected (in terms of nature, severity or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB- approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied AND 
2) suggests that the research places subjects or others (those not directly 
involved in the research such as research staff or family members) at a 
greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized AND 
3) is related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, experience 
or outcome may have been caused by the procedures involved in the 
research). 
4) Serious adverse drug event (either expected or unexpected) occurring in a 
UI subject 
5) If a subject is enrolled by U/VAHCS investigators, the investigator must 
report to the UI IRB either serious adverse drug events or unexpected 
adverse drug events. By definition, these events must be associated with 
the use of the drug. 
6) An unexpected adverse drug event is any adverse drug experience 
(associated with the use of the drug), the frequency, specificity, or severity 
of which is not consistent with the current investigator brochure; or, if an 
investigator brochure is not required or available, the specificity or 
severity of which is not consistent with the risk information provided to 
the subjects and the IRB 
• A serious adverse drug event is any adverse drug experience (associated with 
the use of the drug) occurring at any dose that results in any of the following 
outcomes: 
 
1) Death 

 
 
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2) Life-threatening adverse drug experience 
3) Inpatient hospitalization or prolongation of existing hospitalization 
4) A persistent or significant disability/incapacity 
5) A congenital anomaly/birth defect 
6) Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered a serious adverse drug event 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
• Receipt of new information 
During the course of a study, researchers may become aware of new 
information that would impact a subject’s decision to participate or continue 
participating in the research study. For example, interim analyses of data may 
identify a trend which impacts the safety of subjects or may identify early 
efficacy (benefit) of one of the interventions under study. In addition, results 
from other research studies or changes in standards of practice or care may 
affect conduct of a study and would need to be communicated to research 
subjects. 
 
• Noncompliance 
Noncompliance is a failure to follow the federal regulations with respect to 
protection of human subjects in research or failure to follow the 
determinations of the IRB with respect to conduct of the research as approved 
by the IRB. 
 
Once per year, the IRB is required to review and approve all non-exempt research 
projects at intervals appropriate to the degree of risk, but not less than once a year. 
This is called "continuing review.” Continuing review for non-exempt research is 
required to occur as long as the research remains active for long-term follow-up 
of the research subject, even when the research is permanently closed to the 
enrollment of new subjects and all subjects have completed all research-related 
interventions and to occur when the remaining research activities are limited to 
collection of private identifiable information. 
 
Adverse Event Collection: 
 
The clinical research team is responsible for collecting and recording the research data.  
As the results are collected, all adverse events will be identified after an informed consent 
is signed by the subject. 
 
Throughout the study, during all follow-up visits, in addition to the medical chart review, 
adverse events are to be elicited by the investigator (or designate) by asking the subject 

 
 
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non-leading questions. All AEs and SAEs will be reported to the principal investigator 
(PI) and the PI will determine the final relationship of the event to the investigational 
product.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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X. 
Data Management 
 
The following people/agencies may have access to subject data/records: 
 
• Study team 
• Federal government regulatory agencies 
• Auditing departments of the University of Iowa 
• The National Institute of Health 
 
To protect confidentiality, we will assign each subject a study ID. All records will be 
in a locked cabinet in a locked office or password protected computer system. Data 
and records will be managed as follows: 
• Paper/hard copy records (hard copy surveys, questionnaires, case report 
forms, pictures, etc.) - Whenever possible, subject identifying information will 
be blacked out on all paper or hard copy records and replaced with the 
subject's unique study identifier. Paper records will be stored in a locked file 
cabinet in the study team's locked office.  
• Electronic records (computer files, electronic databases, etc.) – All electronic 
data bases will only be accessed by the study team and available only with a 
username and password assigned to study team by the PI.  
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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XI. 
Subject Safety 
 
• To minimize risks all subjects are carefully pre-screened and screened trying to 
identify any factors that could contribute to increased risk.  
• All testing is completed at University of Iowa Hospitals and Clinics by a very 
experienced and well-trained staff and monitored by the Principal Investigator. 
• All confidential information is kept in locked offices and password protected 
computers only available to study team members.  
• The participant has contact information and study team members available 24/7.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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XII. 
References 
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Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a 
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2-Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L el et. The 
effect of cardiac resynchronization on morbidity and mortality in heart failure. Cardiac 
Resynchronization-Heart Failure (CARE-HF)Study Investigators. N Engl J Med. 
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3. Zareba W, Klein H, Cygankiewicz I, Hall WJ, McNitt S, Brown M el et.Effectiveness of 
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4. Lewinter C, Torp-Pedersen C, Cleland JG, Køber L. Right and left bundle branch block as 
predictors of long-term mortality following myocardial infarction.Eur J Heart Fail. 2011 
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5. Tompkins C, Kutyifa V, McNitt S, Polonsky B, Klein HU, Moss AJ el et. Effect on 
cardiac function of cardiac resynchronization therapy in patients with right bundle branch 
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6. Tanaka H, Adelstein EC, Onishi T, McNamara DM, Schwartzman D, Saba S el et. The 
relationship of QRS morphology and mechanical dyssynchrony to long-term outcome 
following cardiac resynchronization therapy.Eur HeartJ. 2012 Nov;33(21):2680-91. 
7. Kutyifa V, Stockburger M, Daubert JP, Holmqvist F, Olshansky B, Schuger C, Klein H el 
et. PR-Interval Identifies Clinical Response in Patients with Non-LBBB: A MADIT-CRT 
Sub-Study. Circ Arrhythm Electrophysiol. 2014 Jun 24.pii: CIRCEP.113.001299. 
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9. Wells G, Parkash R, Healey J el et. Cardiac resynchronization therapy: a meta-analysis of 
randomized controlled trials.CMAJ. 2011 Mar 8;183(4):421-9 
10. Young JB1, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff el et, Combined 
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11.Egoavil CA, Ho RT, Greenspon AJ, Pavri BB el et.Cardiac resynchronization therapy in 
patients with right bundle branch block: Analysis of pooled data from the MIRACLE and 
Contak CD trials. Heart Rhythm. 2005 Jun;2(6):611-5. 
12. Giudici MC, Schrumpf P, Paul DL, Krupa R, Meierbachtol CJ. Right Ventricular 
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Native Conduction Status on Clinical Results with Right Ventricular Outflow Tract Pacing. 
Am J Cardiol 2003; 91: 240-242. 
14.Byrne MJ, Helm RH, Daya S, Osman NF, Halperin HR, Berger RD el et. Diminished left 
ventricular dyssynchrony and impact of resynchronization in failing hearts with right versus 
left bundle branch block. J Am Coll Cardiol. 2007 Oct9;50(15):1484-90 
15.Aranda JM Jr1, Conti JB, Johnson JW, Petersen-Stejskal S, Curtis AB.Cardiac 
resynchronization therapy in patients with heart failure and conduction abnormalities other 
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16- Finegold JA, Raphael CE, Levy WC, Whinnett YZ, Francis DP. Quantification of 
Survival Gain From Cardiac Resynchronization Therapy. Nonlinear Growth With Time, and 
Greater Gain in Low-Risk Patients, Make Raw Trial Dataan Underestimate of Real-World 
Behavior. J Am Coll Cardiol. 2013 Dec 24;62(25):2406-13