A double-blind crossover study to evaluate the safety and efficacy of adaptive Deep Brain Stimulation delivered through AlphaDBS System in patients with Parkinson*s Disease

Dopaminergic medications are effective in treating PD motor symptoms, but their
efficacy wanes over time. The use of levodopa, the most effective PD
medication, is associated with the development of motor fluctuations in the
near term, and with irreversible motor fluctuations during long-term use. Deep
Brain Stimulation (DBS) uses a medical device, similar to a cardiac pacemaker,
to deliver carefully controlled electrical stimulation to precisely targeted
areas in the basal ganglia.
DBS proved to be effective in improving major Parkinson*s Disease (PD) symptoms
in long-term follow-up studies (Kleiner-Fishman et al, 2003; Krack et al, 2003)
and currently, DBS is the surgical treatment of choice for PD patients with
medication-resistant motor fluctuations, dyskinesias, and refractory tremor. In
particular, DBS of the subthalamic nucleus (STN) has been shown to improve
motor symptoms of PD, levodopa-induced complications and overall quality of
life.
However, current devices deliver DBS with constant stimulation parameters, thus
not controlling typical clinical fluctuations, and do not adapt stimulation
parameters to clinical features, therefore:
1) There is a transient summation of the effects due to DBS and to
pharmacological therapy that leads to a motor (dyskinesias and dystonia) and
non-motor side effects (hypomania or impulse control disorders) in many
patients;
2) The excessive and unnecessary electrical stimulation over time may interfere
with the residual physiological functions of the basal ganglia, thus
contributing (Chen et al, 2006) to the development of neurological
complications such as impairment of speech, balance, and gait, and, possibly,
cognition. In particular, the decline in verbal fluency, which is the most
frequent side effect of STN-DBS, was associated with the influence of
stimulation on sounding neural pathways.
Adaptive DBS (aDBS) strategies have been proposed to automatically adapt
moment-by-moment stimulation parameters to the patient*s clinical symptoms, in
a closed-loop fashion (Marceglia et al, 2007; Priori et al, 2013), thus
avoiding the above-mentioned limitations.
Newronika has developed the «AlphaDBS» System, the first stand-alone system
that can deliver stimulation in a closed-loop adaptive *real-time* fashion,
using a biosignal recorded from the same macro-electrodes routinely implanted
for DBS, as an input variable. AlphaDBS was ideated and created to provide
optimized and personalized control of PD symptoms.

The «AlphaDBS» System records and processes the beta band power and uses it as
an input variable to the adaptive algorithm that computes a new stimulation
amplitude every second, providing the patient only *real* needed stimulation.


However, the information regarding the long-term safety and efficacy of aDBS
remains limited. In facts, so far, studies comparing the efficacy and safety of
aDBS to cDBS had intrinsic limitations, due to technical reasons.
The availability of the AlphaDBSipg, which is the Implantable Pulse Generator
(IPG) component of the «AlphaDBS» System, will allow, for the first time, to
overcome such limitations.

In this first-in-man study, we plan to assess the safety and potential benefits
of aDBS delivered through the «AlphaDBS» System.

The aim of this study is to assess the safety and the potential efficacy of
personalized Local Field Potential (LFP)-based adaptive Deep Brain Stimulation
(aDBS), using the implantable pulse generator (IPG), «AlphaDBS» System, in
Parkinson*s Disease (PD) patients, chronically implanted in subthalamic nucleus
(STN) for DBS, at the time of IPG replacement.
The primary objective will be to evaluate the safety and tolerability of the
«AlphaDBS» System, when used in cDBS and aDBS mode. The determination of safety
and tolerability will be based on the following endpoints:
• Occurrence of device-related adverse events.
• Decrease in the Total Electrical Energy Delivered (TEED) to the patient.
Secondary objective will be to evaluate the potential efficacy of aDBS and
«AlphaDBS» System usability.
Efficacy will be evaluated from the following secondary measures:
• Evaluation of PD-related motor symptoms (i.e. bradykinesia, rigidity and
tremor at rest) and their fluctuations through repeated clinical assessments
(using the Unified Parkinson's Disease Rating Scale -UPDRS- part III).
• Evaluation of dyskinesia and their fluctuations through repeated clinical
assessments (using the Unified Dyskinesia Rating Scale - UDysRS and wearable
Systems).
• Evaluation of *Time On* with and without dyskinesia and *Time Off*, assessed
through Patient Diary.
Usability will be evaluated by means of usability questionnaires.

Exploratory objectives include evaluation of DBS associated deficits, through
the DBS Impairment Scale (DBS-IS) and evaluation of the effects of aDBS on
speech.
*

This is a first-in-man study of the IPG that is part of «AlphaDBS» System, and
it is designed to assess the safety of the device and the potential efficacy of
aDBS closed-loop method in patients with PD.
The study has been designed as a crossover trial that uses conventional DBS
(cDBS) as a control.

The study protocol is organized in two phases: the *short-term follow-up* and
the *long-term follow-up*.

PD patients in need of IPG replacement will be screened to identify for
enrollment eligibility.
For the *short-term follow-up*, randomized patients will undergo 2 days of
experimental sessions (i.e. one per each type of stimulation mode, cDBS and
aDBS), in a well-controlled environment (i.e. during hospitalization). This
part of the study will collect information on safety and efficacy endpoints as
assessed by experienced neurologists.
Patients, who will not experience severe side effects and who will be deemed
suitable by the neurologist, will be eligible to continue in the *long-term
follow-up* phase (i.e. 1 month) in their *home* environment. The «AlphaDBS»
System will deliver the stimulation in aDBS or cDBS mode, for two weeks in each
mode.

The study treatment, adaptive DBS (aDBS), will be tested in comparison with
conventional DBS (cDBS). Following personalized algorithm set up and «AlphaDBS»
System calibration, patients will be randomly assigned to either one of the
stimulation mode sessions (i.e. aDBS or cDBS).

The study will consist of a hospitalization phase in which patients will
undergo surgery for removal of the old IPG, implant of the «AlphaDBS» System
and set up of the personalized algorithm. Then, patients will be randomized to
either aDBS or cDBS stimulation (one day in each mode), and on fourth day
discharged to the second phase of the protocol (home) where they will be
exposed to additional 28 days of DBS (14 days in each mode).

Anticipated adverse events and adverse device effects;
Given the extensive bench testing and animal and clinical studies conducted,
there is a reasonable expectation that the device will be technically
successful and that it will function as intended.
The replacement of a DBS IPG involves risks, and we expect that the patient
implanted with the AlphaDBSipg will be exposed to the same procedure-related
risks reported for other DBS Systems on the market.
These risks are the ones commonly associated with IPG replacement surgery and
described in the protocol at section 7.5.
Possible DBS complications may occur which also are described under section 7.5.

Anticipated clinical benefits
The potential benefits of this study are twofold:
Personal benefits: If patients agree to participate in the study they could or
not experience individual benefits. In fact, the «AlphaDBS» System is the first
DBS system able to deliver adaptive and conventional DBS. The expected benefits
of using the aDBS approach include:
o overall reduction of the electrical energy delivered to the tissues
o overall reduction of the patient*s OFF time (comparable to what observed in
cDBS)
o overall increase of the patient*s ON time without troublesome dyskinesia
o improvement of efficacy in reducing bradykinesia, rigidity, and tremor
(comparable to what observed in cDBS)
o reduction *levodopa-induced dyskinesia*
o improvement in speech, balance, and gait problems related to stimulation.

General benefits: If the results of the trial will be promising. PD patients
will have a new innovate device for DBS that will allow the delivery of
adaptive DBS.
The neurologist and/or the patient will, therefore, have the possibility to
choose between cDBS and aDBS. Patients treated with aDBS could experience a
better quality of life and, a simplification of patient management during the
*stabilization period* normally occurring in patients after DBS implant,
reducing the number of visits and calls to the treating neurologist to fine
tune DBS programming settings. More in general, there will be benefits for the
entire PD community