BradycArdia paCemaKer with AV interval modulation for Blood prEssure treAtmenT (BACKBEAT Trial)

High blood pressure (hypertension) is worldwide one of the the main factors
contributing to cardiovascular diseases and mortality. Cardiovascular risk
doubles for every 20 mmHg increase in systolic blood pressure. The long-term
benefits of reduction in office systolic blood pressure (oSBP) have been
demonstrated in large clinical studies. An analysis of 100 studies evaluating
approximately 600,000 patients demonstrated that a 10mmHg reduction in oSBP is
associated with a risk reduction of major cardiovascular events by 20%,
coronary heart disease by 17%, stroke by
27%, heart failure by 28% and all-cause mortality by 13%.
Although there are numerous medications used for controlling blood pressure,
many patients continue to have persistently high blood pressure despite their
adherence to medical therapies. Investigators have recently turned to alternate
strategies to treat hypertension* in particular, device-based therapies.
Hypertension is the most common condition in the pacemaker patient population
affecting over 70% of these patients. AVIM therapy is a novel pacing algorithm
that when incorporated into a standard dual-chamber cardiac pacemaker system
which enables the existing device to treat hypertension while simultaneously
delivering standard pacing therapy. AVIM therapy is indicated for the reduction
of blood pressure in patients indicated for a dual-chamber pacemaker who also
have uncontrolled hypertension (HTN)
despite the use of anti-hypertensive medications.
Results of the clinical studies performed to date provide evidence of the
safety and efficacy of AVIM therapy and justifies the conduct of this study to
demonstrate safety, effectiveness, and clinical utility (value of a medical
test or treatment in improving patient outcomes) of AVIM therapy. AVIM therapy
is being integrated into the Astra/Azure dual-chamber pacemaker system from
Medtronic, Inc., which is already approved for clinical use by regulatory
bodies worldwide. Rigorous testing has been completed to ensure the
compatibility of AVIM therapy with existing features provided by the
Astra/Azure device. The Astra/Azure pacemaker system incorporating AVIM therapy
will be referred to as the Astra/Azure DR MRI IPG with AVIM therapy.

The primary objective of the study is to determine whether AVIM therapy in
combination with medical therapy is more effective at reducing ambulatory
systolic blood pressure (aSBP) and to determine whether AVIM therapy is safe.

This is a prospective, multinational, randomized, double-blind, clinical trial
evaluating the safety and effectiveness of a novel AV interval modulation
(AVIM) algorithm downloaded into a de novo dual-chamber Medtronic pacemaker.
The study will be conducted in three phases: 1) Screening/Eligibility, 2)
Double-blind Randomized (1 year) and 3) Unblinded (2 years). Patients who are
scheduled to undergo implantation of a, or already have an implanted, de novo
Astra/Azure pacemaker system, who also have uncontrolled hypertension may be
screened for inclusion into this study.
Subjects meeting all eligibility criteria will be scheduled and tested during
the Eligibility Phase; subjects will be assessed for eligibility to be
randomized at the end of the Eligibility Assessment Phase.
Subjects not meeting eligibility criteria for randomization at the end of the
Eligibility Assessment Phase will be exited from the study.
Subjects meeting randomization eligibility criteria will have the
investigational AVIM Therapy RAMware downloaded into the Astra/Azure
implantable pulse generator (IPG). Once downloaded, AVIM therapy is activated
and programmed to settings that achieve a reduction in office systolic blood
pressure (oSBP) of at least 5 mmHg (see further details described in Section
12.17 AVIM Therapy Parameter Setting of the protocol). Eligible subjects will
then enter the double-blind randomized phase and will be randomized 1:1 to
either an active treatment or control group. Subjects in the Treatment Group
will have AVIM therapy turned ON and continue to receive antihypertensive drug
therapy. Subjects in the Control Group will have AVIM therapy turned OFF and
continue to receive antihypertensive drug therapy and standard pacemaker
therapy. Subjects will be followed in the Double-blind Randomized Phase for
12-months and will continue to be followed in an unblinded phase for an
additional 2 years. At the end of the Double-blind Randomized phase, all
subjects will be unblinded and given the option to either remain in the
randomized group assigned or crossover.
All subjects will have the investigational AVIM Therapy RAMware removed from
the pacemaker and exited from the study after the 3-year follow-up is
completed.

The novel AV interval modulation (AVIM) algorithm will be downloaded into a
dual-chamber Medtronic pacemaker.
AVIM Therapy programming can be set to: AVIM OFF or AVIM ON allowing
programming of different parameters related to delivery of AVIM Therapy. AVIM
OFF will result in the pacemaker operating as a standard Azure/Astra DR MRI
IPG.

The AVIM therapy has undergone rigorous bench testing and preliminary
pre-clinical and clinical studies to evaluate its safety and performance. Based
on the results from preclinical studies and in human studies with hypertension
demonstrating a reduction in blood pressure and based on the risk analysis for
Medtronic Azure/Astra DR MRI IPG with AVIM Therapy, the potential benefits in
treating patients with uncontrolled hypertension outweigh the potential risks.
The implant of the Medtronic Azure/Astra DR MRI IPG and pacing leads will occur
as per standard of care. The risks associated with the Medtronic Azure/Astra DR
MRI IPG and pacing leads can be found in the device labelling and User manuals
for the approved devices. After downloading the investigational AVIM therapy,
the Medtronic Azure/Astra DR MRI IPG becomes the investigational device for the
study.
Potential risks associated with the AVIM program are: Too fast of a heart rate,
too slow of a heart rate, development of unusual sensations, feelings or having
a fast beating, fluttering or pounding heart, pain or discomfort, symptoms of
low blood pressure or high blood pressure (including light headedness,
dizziness, loss of consciousness, headache, blurred vision, fatigue or
decreased exercise capacity), development of heart failure and/or a reduction
in left ventricular ejection fraction or shortness of breath on exertion.
Additional risks and burdens specific to the study include data breach due to a
breach in confidentially. However, this will be minimised by carrying out
comprehensive training with the Investigator and study team on data protection.
For the purposes of this study, no subject identifiable data will be collected.
All subjects will be allocated a subject ID number following enrolment into the
study and this number will be used for all study related documentation. The
information collected will only be used for the purposes of this study. The
blood testing required for this study come with discomfort as with any blood
draw and include but are not limited to fainting/light-headedness,
hematoma/bruising, infection, or the requirement of multiple needle punctures
to locate an adequate vein.
In view of the participants clinical condition the risk is not significant, and
the clinical benefit outweighs the long-term risk. The impact of AVIM therapy
of the pacemaker battery life will have no impact on the battery longevity
beyond that for any patient requiring 100% AV pacing.
There may be more time required from participants during the study visits than
would otherwise not be required if they were not participating in the study.
Participants may need to visit the site more frequently and for longer periods
of time and undergo additional blood tests and blood pressure measurements.
All participants will be monitored throughout the study for the detection of
adverse events. All patients will be informed of the potential risks through a
detailed patient information sheet and informed consent form. Participants will
be encouraged to report anything which is troubling them. There may also be
other unforeseeable risks, if any new information becomes during the study,
which could influence participant decision to be included, they will be
informed.
To control or mitigate the risks associated with study participants, qualified
experienced doctors will participants as Investigators along with experienced
research staff to perform study assessments. All those involved in the study
will receive training prior to working on the study. CVs and qualifications
will be checked to ensure those involved in the study are suitably trained and
qualified to perform their delegated responsibilities in the study. All
Investigators and study personnel will be trained on the AVIM Therapy
RAMware-modified dual chamber IPG and its application. All
blood pressure measurements and other tests required by the study will be
performed in a consistent manner with sound research design. Furthermore, AVIM
therapy can be turned off and the AVIM Therapy RAMware can be permanently
removed from the device if required at any point during conduct of the study.