Intraoperative Investigation of a Directional Lead and Local Field Potentials for the Optimization of Stimulation Efficacy
Conditions: Parkinson
Sponsor: Abbott Medical Devices

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
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INVENT 
Intraoperative Investigation of a Directional Lead and Local Field Potentials for the Optimization 
of Stimulation Efficacy 
CRD_931 
Study Document No: SJM-CIP-10219 
Version A 
Date: 9/29/17 
Clinical Investigation Plan (CIP) 
 
 
Sponsor  
 
Abbott, Inc. 
                                       6901 Preston Road 
                                       Plano, TX  75024 
                                       USA 
                                       Tel: 972 309 8000 
                                       Fax: 972 309 8150 
 
 
Coordinating  
 
 
Nuri Firat Ince 
Investigator                             
University of Houston 
       
 
 
 
Department of Biomedical Engineering, Assistant Professor 
       
 
 
 
University of Houston 
HBS—Building 592, Rm 334 
4849 Calhoun Rd.  
Houston , TX 77204 
 
        
 
 
 
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation. 
 
 
Principal Investigator 
 
Printed name: 
Signature: 
Date: 
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
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Coordinating Investigator/ National Investigator 
 
SIGNATURE PAGE 
 
 
 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation.  
 
 
Coordinating Investigator/ National Investigator   
 
Printed name: 
Signature: 
Date: 
 
 
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
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Table of Contents 
 
1 
Synopsis ................................................................................................................................................. 7 
 
Objective(s) ................................................................................................................................... 7 
 
Devices Used ................................................................................................................................ 7 
 
Indications for Use ......................................................................................................................... 7 
 
Design ........................................................................................................................................... 7 
 
Endpoints ....................................................................................................................................... 8 
1.5.1 
Primary Endpoints ..................................................................................................................... 8 
1.5.2 
Secondary Endpoints ................................................................................................................ 8 
 
Study Population ........................................................................................................................... 8 
 
Inclusion/Exclusion Criteria ........................................................................................................... 8 
1.7.1 
Inclusion Criteria ........................................................................................................................ 8 
1.7.2 
Exclusion Criteria ....................................................................................................................... 8 
 
Enrollment ..................................................................................................................................... 8 
 
Study Assessments ....................................................................................................................... 8 
2 
Introduction........................................................................................................................................... 10 
3 
Background and Justification for Clinical Investigation ........................................................................ 10 
4 
Device(s) Under Investigation .............................................................................................................. 14 
 
Identification and Description of the Devices under investigation ............................................... 14 
4.1.1 
Identification ............................................................................................................................ 14 
4.1.2 
Device Description and Intended Purpose .............................................................................. 14 
4.1.3 
Device Handling and Storage .................................................................................................. 14 
 
Devices Accountability ................................................................................................................ 14 
5 
Clinical Investigation Design ................................................................................................................ 14 
 
Clinical Investigation Design ....................................................................................................... 14 
 
Objectives .................................................................................................................................... 15 
5.2.1 
Primary Objectives .................................................................................................................. 15 
5.2.2 
Secondary Objectives.............................................................................................................. 15 
 
Endpoints ..................................................................................................................................... 16 
5.3.1 
Primary Endpoint ..................................................................................................................... 16 
5.3.2 
Secondary Endpoint ................................................................................................................ 16 
 
Study Population ......................................................................................................................... 16 
5.4.1 
Inclusion Criteria ...................................................................................................................... 16 
5.4.2 
Exclusion Criteria ..................................................................................................................... 16 
6 
Procedures ........................................................................................................................................... 17 
 
Informed Consent Process .......................................................................................................... 17 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 5 of 35 
 
 
Point of Enrollment ...................................................................................................................... 18 
 
Scheduled Procedures ................................................................................................................ 18 
6.3.1 
Implant/Procedure ................................................................................................................... 18 
6.3.2 
Additional Visits ....................................................................................................................... 19 
 
Unscheduled Visits ...................................................................................................................... 19 
 
Description of Activities Performed by Sponsor Representatives ............................................... 20 
 
Subject Study Completion ........................................................................................................... 20 
 
Subject Withdrawal ...................................................................................................................... 20 
7 
Statistical Considerations ..................................................................................................................... 20 
 
Hypotheses .................................................................................................................................. 21 
7.1.1 
Primary Endpoint Hypothesis .................................................................................................. 21 
7.1.2 
Secondary [Safety/Effectiveness] Endpoint Hypothesis(es) ................................................... 22 
 
Justification of Clinical Investigation Design ............................................................................... 22 
 
Multiplicity .................................................................................................................................... 22 
 
Overall Sample Size .................................................................................................................... 23 
 
Deviations from Statistical Plan ................................................................................................... 23 
8 
Risks and Benefits ............................................................................................................................... 23 
 
Risks Associated with the Device Under Investigation ............................................................... 23 
8.1.1 
Anticipated Adverse Device Effects ........................................................................................ 23 
8.1.2 
Risks Associated with Clinical Investigation Assessments ..................................................... 24 
 
Risk Control Measures ................................................................................................................ 24 
 
Possible interactions with concomitant treatments ..................................................................... 24 
 
Anticipated Benefits ..................................................................................................................... 25 
 
Risk-to-Benefit Rationale ............................................................................................................. 25 
 
History of Device Modifications or Recall .................................................................................... 25 
9 
Requirements for Investigator Records and Reports ........................................................................... 25 
 
Deviations from CIP..................................................................................................................... 25 
 
Safety Reporting .......................................................................................................................... 25 
9.2.1 
Subject Death .......................................................................................................................... 26 
9.2.2 
Complaints ............................................................................................................................... 26 
 
Source records ............................................................................................................................ 26 
 
Records Retention ....................................................................................................................... 26 
10 Clinical Data Handling .......................................................................................................................... 26 
 
Protection of Personally Identifiable Information ......................................................................... 26 
 
Data Management Plan ............................................................................................................... 27 
 
Document and Data Control ........................................................................................................ 27 
10.3.1 
Traceability of Documents and Data ................................................................................... 27 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
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10.3.2 
Recording Data .................................................................................................................... 27 
11 Monitoring............................................................................................................................................. 27 
12 Compliance Statement ......................................................................................................................... 27 
 
Statement of Compliance ............................................................................................................ 27 
 
Quality Assurance Audits and Regulatory Inspections ............................................................... 28 
 
Repeated and Serious Non-Compliance ..................................................................................... 28 
13 Suspension or Premature Termination of the Clinical Investigation .................................................... 28 
14 Clinical Investigation Conclusion ......................................................................................................... 29 
15 Publication Policy ................................................................................................................................. 29 
Appendix A: CIP Revisions ......................................................................................................................... 30 
Appendix B: Definitions ............................................................................................................................... 31 
Appendix C: Bibliography ............................................................................................................................ 33 
Appendix E: Case Report Form .................................................................................................................. 34 
Appendix F: Informed Consent Form .......................................................................................................... 35 
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 7 of 35 
 
1 
Synopsis 
 
Objective(s) 
The current study aims to explore the functional use of LFPs recorded intraoperatively for the optimization 
of a directional DBS lead programming  
 
Aim-1: To determine whether intraoperative LFPs recorded from the segmented DBS electrode 
can predict the optimal stimulation parameters. 
 
Aim-2: Compare the therapeutic window for stimulation delivered through directional and 
conventional leads and determine if the spatiospectral LFP patterns correlate with the presence of 
stimulation side effects.  
 
Devices Used 
 
The following devices will be used in this clinical investigation: 
Device name 
Model/Type 
Manufacturer 
Region/ Country 
Investigational or 
Market Released 
Infinity IPGs 
6660 -3 
Abbott 
US 
Market released 
Infinity Directional 
Leads 
6170-3 
Abbott 
US 
Market released 
Infinity System 
Extensions 
6371-3 
Abbott 
US 
Market released 
GuardianTM Burr 
Hole Cover 
6010 
Abbott 
US 
Market released 
Clinician 
Programmer 
3872 & 3874 
Abbott 
US 
Market released 
Patient Controller 
6883 & 3875 
Abbott 
US  
Market released 
DBS EPG 
6599 
Abbott 
US  
Market released 
8-Channel Adapters 
2311 & 2316 
Abbott 
US 
Market released 
Multilead Trial Cable 
3014 
Abbott 
US 
Market released 
 
 
Indications for Use 
 
The Infinity directional leads are indicated for use in DBS as treatment for PD symptoms. 
 
Design 
This is a feasibility study designed to evaluate the usefulness of intraoperative LFP recordings obtained 
from the implanted DBS lead to predict ideal stimulation parameters.  
Additionally this study will compare the therapeutic window for stimulation delivered through directional 
and conventional leads and determine if the spatiospectral LFP patterns correlate with the presence of 
stimulation side effects. 
 
Approximately 8 subjects will be enrolled in this clinical investigation. The clinical investigation will be 
conducted at 2 centers in the USA. 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 8 of 35 
 
Subjects participating in this clinical investigation will monitored during DBS implant procedure and 
programming. The expected duration of enrollment is 8 months. The total duration of the clinical 
investigation is expected to be 1 year. 
 
Endpoints 
The overall goal of the study is to investigate LFP analysis as a strategic tool in the operating room (OR) 
setting and to establish the relationship between LFPs and DBS efficacy and side effects. 
1.5.1 
Primary Endpoints 
Concordance between LFP derived predictions and clinically optimized stimulation parameters  
 
1.5.2 
Secondary Endpoints 
Characteristic of the LFP signals correlating to presence of side effects 
 
 
Study Population 
In this study we will explore the predictive capacity of LFPs recorded from STN. In total, 8 patients 
undergoing bilateral STN DBS and part of the PROGRESS study will be enrolled for this investigation 
over a 1-year period. The current surgical case load at BCM supports this level of enrollment. The details 
of implantation procedures and blinded trial design are given in the following sections. 
 
Inclusion/Exclusion Criteria 
1.7.1 
Inclusion Criteria 
• 
Patient currently enrolled in the PROGRESS study 
• 
Age 18-70 years 
• 
Ability to provide informed consent 
• 
Diagnosis of idiopathic Parkinson’s disease, and DBS consensus team review supporting the 
placement of STN DBS. 
1.7.2 
Exclusion Criteria 
• 
Subject is not a surgical candidate; 
• 
In the Investigator’s opinion the subject unable to tolerate multiple programming sessions within a 
single setting; 
• 
Subject unable to comply with the follow-up schedule 
 
Enrollment 
A patient becomes a subject once he/she has been fully informed about the study, has agreed to 
participate, signed & dated the consent. 
 
Study Assessments 
LFP recordings will be collected from the implanted DBS lead at the end of the DBS implantation 
procedure. Simultaneously other biomedical and physiological signals collected with a variety of sensors, 
including a 2-channel bipolar electrocardiogram, 4 channel electromyogram (EMG; 2 upper and 2 lower 
limbs), and two 3-axis accelerometers attached to contra-lateral limbs. 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 9 of 35 
 
The optimal stimulation parameters, selected using standard clinical programming algorithms, will be 
collected for comparison with the predictions obtained from the analysis of the data collected during the 
DBS implant procedure. 
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 10 of 35 
 
2 
Introduction 
The current study aims to explore the functional use of LFPs recorded intraoperatively for the optimization 
of a directional DBS lead programming via the following two aims: 
 
Aim-1: To determine whether intraoperative LFPs recorded from the segmented DBS electrode can 
predict the optimal stimulation parameters. 
 
Aim-2: Compare the therapeutic window for stimulation delivered through directional and conventional 
leads and determine if the spatiospectral LFP patterns correlate with the presence of stimulation side 
effects.  
 
This clinical investigation will be performed in the U.S.A. and is sponsored by Abbott. 
 
This clinical investigation will be conducted in accordance with this CIP. All parties involved in the conduct 
of the clinical investigation will be qualified by education, training, or experience to perform their tasks and 
this training will be documented appropriately. 
3 
Background and Justification for Clinical Investigation 
The efficacy of deep brain stimulation (DBS) has been established and it is now the most commonly used 
surgical treatment for patients with Parkinson’s disease (PD) in the U.S. DBS provides patients with 
moderate to advanced symptoms a better quality of life than with medication alone (Deuschl et al., 2006; 
Williams et al., 2010). There is no consensus as to the optimal site for the active electrode of the DBS 
lead in the subthalamic nucleus (STN). Additionally, patients receive differing therapeutic benefit with 
varying DBS parameters. Consequently, quantitative and objective methods for determining optimal 
electrode location and stimulation parameters are needed (Mera et al., 2011). STN stimulation can result 
in side effects arising from the spread of stimulation to surrounding structures (Richardson, et al., 2009). 
Moreover, sub-optimal positioning of DBS electrodes accounts for up to 40% of cases of inadequate 
efficacy of stimulation postoperatively (Okun et al., 2005). Thus, the clinical efficacy of DBS depends 
critically on accurate localization of the STN and generated stimulation field. 
 
DBS surgery in PD involves the stereotactic implantation of a macroelectrode into a pre-determined target 
region, selected based on the indication being treated. The indirect, or consensus target coordinates are 
then modified based on preoperative stereotactic imaging and/or intraoperative electrophysiological 
techniques. The most commonly employed electrophysiological techniques include microelectrode 
recording and macrostimulation through the DBS electrode. Microelectrode single unit activity (SUA) 
recording allows the identification of individual neurons that are characteristic of the target of interest, by 
virtue of cellular firing rate, amplitude, pattern, and distance from the cortical surface. The DBS electrode, 
which typically consists of four platinum-iridium contacts, is subsequently implanted based on the 
microelectrode findings. Implantation of DBS electrodes also makes it possible to assess the neural 
activity of a population of neurons from deep brain structures. Therefore, local field potentials (LFPs) can 
be used strategically to study the dynamics of deep brain structures and develop novel technologies for 
the improvement of DBS therapy in a closed loop fashion.  
Our hypothesis are that a) current steering  will yield fewer side effects than omnidirectional stimulation 
and b) the knowledge about the spatial distribution of LFPs assessed with segmented leads can be used 
to select certain stimulation parameters.  
 
With these motivations we will study the following aims to explore the functional use of LFPs recorded 
intraoperatively for the optimization of a directional DBS lead programming. A schematic diagram 
representing our proposed work is also given in Fig.1. 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 11 of 35 
 
Studies measuring and analyzing the LFPs in the STN indicate that excessive synchronization of 
oscillatory activity exists in the beta frequency band (8–30Hz) and can be used as a possible 
pathophysiological marker of the Parkinsonian state in human patients with PD (Brown et al.,2001; 
Williams et al., 2002; Kuhn et al.,2005). It is well recognized that PD patients in the “off” medication state 
demonstrate increased power in beta band oscillations at rest in both the STN and the GPi (Brown and 
Williams, 2005). Levodopa intake, and subsequent motor improvement, correlates with the power 
decrease of the beta band in both the STN (Kuhn et al, 2009) and GPi (Brown et al, 2001). However, 
limited research explored the functional use of LFPs for the optimization of DBS in the clinical setting. The 
latest research executed on a small population of human subjects indicates that the LFP activity recorded 
post operatively can serve as a neuro-biomarker to predict the optimal contact for stimulation (Ince et al., 
2010). 
 
With this motivation, the LFPs recorded from the contacts of the segmented DBS electrode located in the 
STN will be used to investigate whether the assessed activity during the surgery can be correlated with 
the magnitude of symptom severity and improvement following stimulation. Specifically, through a 
blinded study, we will investigate whether the contacts with excessive LFP activity at various 
bands seen intra-operatively match the contacts selected clinically for DBS programming. If they 
do not match, contributing factors will be explored. A sample dataset representing the predictive 
capability of intra-operative STN LFPs to select the clinically optimal stimulation contact is given in Fig.2. 
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 12 of 35 
 
E 
 
 
 
 
 F 
 
 
             G     
     
 
      
     
 
H 
 
 
Fig.1. The schematic diagram of our blinded study design is given in the top image. The LFP and SUA recording 
will be obtained in the OR and information obtained from both modalities will be used for track selection. 
Intraoperative LFP recordings will be obtained simultaneously with SUA from three trajectories identified by 
stereotactic imaging (A). The microelectrodes will be inserted towards the estimated target with a Neurodrive (B) to 
localize characteristic SUA or excessive LFP activity in the STN (D). After the identification of optimal track and 
depth, a directional DBS electrode (E) with 1-3-3-1 configuration will be implanted temporarily. LFP recordings will 
be obtained from all 8 contacts of the directional lead and will be processed in real-time intraoperatively with a 
system developed in Dr. Ince’s laboratory. The neurologist will be blinded to these LFP recordings (F). The 
therapeutic window will be studied with the implanted electrode by generation of the stimulation with 6 
unidirectional and one omnidirectional pattern (G and E). The outcome of the unidirectional stimulation will be 
   
   
   
   
   
   
   
 
 
 
Legend 
Stimulation contacts 
Recording contacts 
  (during stimulation) 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
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A                                                                                                    B 
 
C 
 
 
 
 
 
        
 
 
 
D 
 
Fig.3. (A) Bipolar raw STN LFP recordings from Pt-1. (B)  The bipolar LFP spectra from Pt-1. Note, the 
maximum power in beta band occurs in the E0-E1 bipolar derivation, which also correlated with the 
optimal stimulation contact setting. (C) Normalized β-band power (dB scale) in bipolar DBS electrode 
contacts from four patients. The bipolar contacts with optimal stimulation benefit are marked with blue 
arrows.  (D) The schematic on the right shows the all three bipolar LFP derivations (E0-E1, E1-E2 and 
E2-E3)
 
 
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 14 of 35 
 
4 
Device(s) Under Investigation 
 
Identification and Description of the Devices under investigation 
4.1.1 
Identification 
No devices are under investigation in this study. In this study we seek to evaluate the feasibility of using 
LFP recorded during DBS lead implant as support to programming of DBS stimulation parameters. This 
will be performed using custom software for analysis of electrophysiological data developed by Prof. Ince. 
 
Table 1: Identification of Devices under Investigation 
 
Device name 
Model/Type 
Manufacturer 
Region/ Country 
Investigational or 
Market Released 
Infinity IPGs 
6660 -3 
Abbott 
US 
Market released 
Infinity Directional 
Leads 
6170-3 
Abbott 
US 
Market released 
Infinity System 
Extensions 
6371-3 
Abbott 
US 
Market released 
GuardianTM Burr 
Hole Cover 
6010 
Abbott 
US 
Market released 
Clinician 
Programmer 
3872 & 3874 
Abbott 
US 
Market released 
Patient Controller 
6883 & 3875 
Abbott 
US  
Market released 
DBS EPG 
6599 
Abbott 
US  
Market released 
8-Channel Adapters 
2311 & 2316 
Abbott 
US 
Market released 
Multilead Trial Cable 
3014 
Abbott 
US 
Market released 
 
4.1.2 
Device Description and Intended Purpose 
 
The Infinity device and all the devices indicated in table 1 are indicated for use in the treatment of 
Parkinson’s disease.  
4.1.3 
Device Handling and Storage 
Sponsor requires all investigational products be stored, according to the labeling and Instructions for Use, 
in a secure area to prevent unauthorized access or use. 
 
Devices Accountability 
Post market study not requiring device accountability. 
 
5 
Clinical Investigation Design 
 
Clinical Investigation Design 
This is a prospective single center feasibility trial aimed at evaluating the functional use of LFPs recorded 
intraoperatively for the optimization of a directional DBS lead programming. 
All participants will undergo DBS implant procedure according to standard clinical practice. After lead 
implant LFP will be recorded from the DBS lead for 1min in resting and hand movement states, together 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 15 of 35 
 
with additional physiological signals. The efficacy of stimulation will be validated intraoperatively with 
concurrent testing of parkinsonian features and the absence of stimulation side-effects, per clinical 
routine.  
The recorded data will be converted to Matlab (Mathworks, Natick MA) format, as described previously 
(Ince et al, 2010) for further analysis. The LFP data will be processed offline, using state-of-the-art signal 
processing and spectrum estimation techniques, to identify novel neuro-markers that will be used for the 
prediction of prediction of optimal stimulation contacts and correlation with the symptoms of the patient.  
 
We will quantify the relief of symptoms through steered stimulation by contrasting the UPDRS scores 
before and after DBS in the outpatient clinical settings according to procedures described in the 
PROGRESS study for both directional and omnidirectional stimulation, and for identification of the 
therapeutic window. 
 
In total, 8 patients undergoing bilateral STN DBS and part of the PROGRESS study will be enrolled for 
this investigation over a 1-year period. The current surgical case load at BCM supports this level of 
enrollment. 
This study will be conducted in two centers in the U.S.A. 
 
 
Objectives 
5.2.1 
Primary Objectives 
To determine whether intraoperative LFPs recorded from the segmented DBS electrode can predict the 
optimal stimulation parameters.  
Studies measuring and analyzing the LFPs in the STN indicate that excessive synchronization of 
oscillatory activity exists in the beta frequency band (8–30Hz) and can be used as a possible 
pathophysiological marker of the Parkinsonian state in human patients with PD (Brown et al.,2001; 
Williams et al., 2002; Kuhn et al.,2005). It is well recognized that PD patients in the “off” medication state 
demonstrate increased power in beta band oscillations at rest in both the STN and the GPi (Brown and 
Williams, 2005). Levodopa intake, and subsequent motor improvement, correlates with the power 
decrease of the beta band in both the STN (Kuhn et al, 2009) and GPi (Brown et al, 2001). However, 
limited research explored the functional use of LFPs for the optimization of DBS in the clinical setting. The 
latest research executed on a small population of human subjects indicates that the LFP activity recorded 
post operatively can serve as a neuro-biomarker to predict the optimal contact for stimulation (Ince et al., 
2010). 
With this motivation, the LFPs recorded from the contacts of the segmented DBS electrode located in the 
STN will be used to investigate whether the assessed activity during the surgery can be correlated with 
the magnitude of symptom severity and improvement following stimulation. Specifically, through a blinded 
study, we will investigate whether the contacts with excessive LFP activity at various bands seen intra-
operatively match the contacts selected clinically for DBS programming. If they do not match, contributing 
factors will be explored. A sample dataset representing the predictive capability of intra-operative STN 
LFPs to select the clinically optimal stimulation contact is given in Fig.2. 
5.2.2 
Secondary Objectives 
Compare the therapeutic window for stimulation delivered through directional and conventional leads and 
determine if the spatiospectral LFP patterns correlate with the presence of stimulation side effects.  
As one experimenter adjusts the stimulation parameters, a blinded rater will record the therapeutic 
window (TW) from  the minimum amount of current required to provide a meaningful improvement in 
motor symptoms to the maximum current that could be delivered without producing adverse effects, such 
as dysarthria, focal muscle contractions or paraesthesias. The TW of directional stimulation will be 
compared to omnidirectional stimulation. Using this data (acquired through long-term directional and 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 16 of 35 
 
omnidirectional programming as part of the PROGRESS study), as well as the 3D distribution of the LFP 
recordings, we will investigate the relationship between the two when an omnidirectional stimulation field 
is generated. For example, a side effect may be more likely to occur if the clinical stimulation field 
includes an area outside the spatial distribution of LFPs with select characteristics.  
 
 
Endpoints 
There is one primary endpoint and one secondary endpoint in this clinical investigation. 
5.3.1 
Primary Endpoint 
Concordance between LFP derived predictions and clinically optimized stimulation parameters 
In this project we will establish the feasibility of recording LFP data intra-operatively from DBS electrode 
contacts using a multi-channel, high throughput data acquisition system and investigate if patterns in LFP 
can be used to select the optimal contacts for patient programming. Establishing the role of identifying 
and localizing  LFP patterns intraoperatively can play an essential role in assisting the clinician who is 
programming the patient to select the optimal contact, especially when electrodes with multiple contacts 
(>8) are employed during DBS therapy. In this scenario, conventional techniques employing systematic 
contact evaluations in various combinations will be impractical due to time constraints.  
The recently developed directional lead of SJM with 1-3-3-1 configuration offers the possibility of 
recording LFP activity from multiple directions. The primary utility of the segmented electrode is to steer 
the stimulation such that the side effects can be minimized. However, multiple contacts (n=8) on the 
electrode increase the programming complexity. In this project, we aim to determine in a blinded manner 
whether LFPs can guide programming. The outcomes of this pilot project will establish the scientific basis 
for whether LFPs recorded from a segmented electrode can be used for clinical decision making and to 
fine tune stimulation parameters.  
5.3.2 
Secondary Endpoint 
Characteristic of the LFP signals correlating to presence of side effects. 
 
Study Population 
In this study we will explore the predictive capacity of LFPs recorded from STN. In total, 8 patients 
undergoing bilateral STN DBS and part of the PROGRESS study will be enrolled for this investigation 
over a 1-year period. The current surgical case load at BCM supports this level of enrollment. The details 
of implantation procedures and blinded trial design are given in the following sections. 
5.4.1 
Inclusion Criteria 
 
To participate in this clinical investigation, the subject must meet all of the following inclusion criteria: 
• 
Patient currently enrolled in the PROGRESS study 
• 
Age 18-70 years 
• 
Ability to provide informed consent 
• 
Diagnosis of idiopathic Parkinson’s disease, and DBS consensus team review supporting the 
placement of STN DBS. 
5.4.2 
Exclusion Criteria 
 
Subjects who meet any of the following exclusion criteria must be excluded from the clinical investigation: 
• 
Subject is not a surgical candidate; 
• 
In the Investigator’s opinion the subject unable to tolerate multiple programming sessions within a 
single setting; 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 17 of 35 
 
• 
Subject unable to comply with the follow-up schedule 
 
6 
Procedures 
Approval from the Sponsor must be received prior to initiating study procedures. 
 
Enrolled subjects (as defined in section 6.2) will undergo DBS implant with the Infinity device according to 
standard clinical practice. During implantation procedure LFP will be recorded from the DBS leads 
contacts together with additional biometric measurements. The efficacy of stimulation will be validated 
intraoperatively with concurrent testing of parkinsonian features and the absence of stimulation side-
effects, per clinical routine.  
We will quantify the relief of symptoms through steered stimulation by contrasting the UPDRS scores 
before and after DBS in the outpatient clinical settings according to procedures described in the 
PROGRESS study for both directional and omnidirectional stimulation, and for identification of the 
therapeutic window. All subjects will undergo rigorous rating-scale-based assessment of the severity of 
their neurologic symptoms “off” and “on” PD medications, using the practically defined off state (CAPSIT-
PD). Programming will be performed by an experienced clinical practitioner who is blinded to the LFP 
recordings and their analysis. 
Following completion of this study, patients care will continue according to the PROGRESS study.  
 
The following sections provide a detailed description of procedures required by this CIP. 
 
Informed Consent Process 
The Principal Investigator or his/her authorized designee will conduct the Informed Consent Process, as 
required by applicable regulations and the center’s IRB/EC. This process will include a verbal discussion 
with the subject on all aspects of the clinical investigation that are relevant to the subject’s decision to 
participate, such as details of clinical investigation procedures, anticipated benefits, and potential risks of 
clinical investigation participation. During the discussion, the Principal Investigator or his/her authorized 
designee will avoid any improper influence on the subject and will respect subject’s legal rights. The 
subject shall be provided with the informed consent form written in a language that is understandable to 
the subject and has been approved by the center’s IRB/EC. The subject shall have adequate time to 
review, ask questions and consider participation. 
 
If the subject agrees to participate, the Informed Consent form must be signed and dated by the subject 
and by the person obtaining the consent. The signed original will be filed in the subject’s hospital or 
research charts, and a copy will be provided to the subject. 
 
The Principal Investigator or his/her authorized designee will document the informed consent process in 
the subject’s hospital and/or research charts. The date of signature will be entered on an applicable Case 
Report Form (CRF). 
 
Failure to obtain informed consent from a subject prior to clinical investigation enrollment should be 
reported to Sponsor within 5 working days and to the reviewing center’s IRB/EC according to the IRB’s/ 
EC’s reporting requirements. 
 
If, during the clinical investigation, new information becomes available that can significantly affect a 
subject's future health and medical care, the Principal Investigator or his/her authorized designee will 
provide this information to the subject. If relevant, the subject will be asked to confirm their continuing 
informed consent in writing. 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 18 of 35 
 
 
Point of Enrollment 
Subject is considered enrolled in the clinical investigation from the moment the subject has provided a 
written Informed Consent and has been confirmed to meet all inclusion criteria and none of the exclusion 
criteria. 
 
The Principal Investigator or delegated study personnel will record enrollment information (name of the 
clinical investigation, date of consent and Inclusion/exclusion information) in the hospital records and 
complete and submit an applicable CRF in a timely manner. 
 
Notification of enrollment to the Sponsor is considered to have occurred when the Sponsor has received 
the applicable CRF. 
 
Scheduled Procedures 
The Principal Investigator is responsible for ensuring all clinical investigation data is collected as required 
per CIP scheduled procedures. 
 
6.3.1 
Implant/Procedure 
 
All participating subjects will undergo 3.0T MRI and CT scans to be used for surgical planning. The 
imaging protocol will consist of anatomical imaging using susceptibility-weighted imaging (SWI), T1-, and 
T2-weighted sequences. The brain MRI (Stealth Station, Medtronic) will be fused in stereotactic space, to 
the CT to determine the initial electrode trajectory to STN and confirm final electrode location. 
 
Patients will undergo a preoperative stereotactic MRI as described above. On the morning of surgery, 
patients will undergo placement of the Leksell frame under local anesthesia, and will then undergo a 
stereotactic CT scan. Three simultaneous microelectrode recording tracks will be performed, with one 
electrode oriented along the CT/MRI-derived electrode trajectory, one 2-mm anterior, and one 2-mm 
lateral. 
 
Single unit activity (SUA) and LFP recordings will begin at 20mm above the presumptive target and three 
microelectrodes will be advanced through the target to a position 3-mm below the intended target, in 1mm 
increments until 10mm above target. Then reduce increment to less than 0.5mm until the electrode 
reaches 3mm below the target. The positions of initial 3-microelectrodes will be modified if necessary due 
to the lack of excessive beta band activity. At each depth, microelectrodes will be used to record both 
LFP and SUA for 30 seconds. 
 
The neurosurgeon will use standard clinical technique for localizing the STN, via real-time auditory and 
visual analysis of the SUA. The dorsal, ventral, and posterior borders of the STN will thus be identified, 
and STN neurons examined for movement-responsive receptive fields. The ventral border of the STN will 
be selected as the desired depth for the tip of the chronic DBS electrode. Our previous recordings 
indicate that STN can be identified with an excessive beta band activity of LFPs. Therefore, the optimal 
trajectory and electrode depth will be selected based on the excessive LFP activity and combination of 
SUA signal analysis.  
 
Then the directional lead will be implanted and LFP signals will be recorded from all 8 contacts of the 
macroelectrode with 1-3-3-1 configuration. The LFP signal will be recorded from the target for 1min in 
resting and hand movement states (Aim-1). During these recordings, the neurologist who will test patient 
programming will be blinded to LFP data. Therefore, in each patient the optimal stimulation contacts will 
be selected without any influence from the LFP analysis. 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 19 of 35 
 
The LFP recordings will be obtained using the gHIamp biosignal amplifier (Gtec, Inc. Austria) at 2.4 kHz 
and 24 bit resolution. The depth information will be obtained from the Neurodrive (Alpha Omega, 
Nazareth, Israel), through a custom Ethernet based interface which was previously developed in Dr. 
Ince’s lab. Besides neural activity, we will record other biomedical and physiological signals with a variety 
of sensors, including a 2-channel bipolar electrocardiogram, 4 channel electromyogram (EMG; 2 upper 
and 2 lower limbs), and two 3-axis accelerometers attached to contra-lateral limbs. These signals will be 
entered into the multipurpose neural data acquisition system in order to synchronize behavior with the 
neural data. Resting and movement periods of the recording will be identified from the EMG and wireless 
3-axis accelerometer sensors. The recorded data will be converted to Matlab (Mathworks, Natick MA) 
format, as described previously (Ince et al, 2010) for further analysis. The LFP data will be processed 
offline, using state-of-the-art signal processing and spectrum estimation techniques, to identify novel 
neuro-markers that will be used for the prediction of prediction of optimal stimulation contacts and 
correlation with the symptoms of the patient.  
 
The efficacy of stimulation will be validated intraoperatively with concurrent testing of parkinsonian 
features and the absence of stimulation side-effects, per clinical routine. For instance, the presence of 
low-threshold side effects of stimulation, indicating electrode position too close to an adjacent structure—
e.g., internal capsule or medial lemniscus or nucleus of cranial nerve III, when STN is the desired target—
would require repositioning in order for the electrode to be clinically useful. 
 
6.3.2 
Additional Visits 
Quantification of the relief of symptoms and therapeutic window with omnidirectional and directional 
stimulation will be obtained in the outpatient setting as part and according to the procedures described in 
the PROGRESS study, during the appropriate follow up visits.  
 
 
Unscheduled Visits 
These visits will be documented as part of the PROGRESS study. 
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 20 of 35 
 
 
Table 2: List of all clinical investigation specific tests and procedures 
 
                Visit 
 
 
Study Activity 
Enrollment & Baseline 
Implant Procedure 
Initial Programming 
Informed Consent 
Process 
X 
 
 
Enrollment 
X 
 
 
Inclusion/Exclusion 
X 
 
 
DBS implant 
 
X 
 
Local field potential 
recordings 
 
X 
 
Termination 
(X) 
(X) 
(X) 
Death 
(X) 
(X) 
(X) 
(X) If applicable 
 
Description of Activities Performed by Sponsor Representatives  
While Sponsor representatives may perform these activities, the Principal Investigator remains 
responsible for ensuring all clinical investigation data is collected as required per CIP. 
 
Subject Study Completion 
Subject participation in the clinical investigation will conclude upon completion of the 12-month visit. Upon 
completion of subject participation in the clinical investigation, the subject will return to standard of care. 
 
Subject Withdrawal 
Subjects must be informed about their right to withdraw from the clinical investigation at any time and for 
any reason without sanction, penalty or loss of benefits to which the subject is otherwise entitled. 
Withdrawal from the clinical investigation will not jeopardize their future medical care or relationship with 
the investigator. Subjects will be requested to specify the reason for the request to withdraw. The 
investigator must make all reasonable efforts to retain the subject in the clinical investigation until 
completion of the clinical investigation. 
 
A subject will be considered ‘Lost to Follow-up’ after 3 number of missed visit(s) and a minimum of two 
unsuccessful phone calls from investigational site personnel to the subject or contact to schedule the next 
follow-up visit. These two phone calls must be documented in the subject’s hospital records. If the subject 
is deemed lost to follow-up a letter should be sent to the subject’s last known address or to the subject’s 
general practitioner (GP) and a copy of the letter must be maintained in the subject’s hospital records. 
 
In case of subject withdrawal, the site should make attempts to schedule the subject for a final study visit. 
At this final study visit, the subject will undergo the following assessments: 
• 
Termination 
 
7 
Statistical Considerations 
The following section describes the statistical methods for the clinical investigation and justification of the 
design. Additional details on statistical analyses, including sensitivity analyses, poolability analyses, 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 21 of 35 
 
subgroup analyses and analysis of descriptive endpoint(s) may be maintained in a separate Statistical 
Analysis Plan (SAP).  
 
Hypotheses 
The current study aims to explore the functional use of LFPs recorded intraoperatively for the optimization 
of a directional DBS lead programming  
 
Aim-1: To determine whether intraoperative LFPs recorded from the segmented DBS electrode 
can predict the optimal stimulation parameters. 
 
Aim-2: Compare the therapeutic window for stimulation delivered through directional and 
conventional leads and determine if the spatiospectral LFP patterns correlate with the presence of 
stimulation side effects.   
7.1.1 
Primary Endpoint Hypothesis 
To determine whether intraoperative LFPs recorded from the segmented DBS electrode can predict the 
optimal stimulation parameters. 
7.1.1.1 
Analysis Methodology  
 
To identify the location of the DBS electrode and its contacts as well as the directionality of the 
segmented contacts, the intra-operative and postoperative CT and 1.5T MRI scans will be merged in 
stereotactic space to the preoperative imaging dataset, using the Cranial Cloud interface.   
 
Artifact-free LFP segments at each depth will be identified by visual inspection of sensor data and video 
recording, and, will be subjected to spectral analysis. Power spectra of the monopolar and bipolar LFP 
signals will be computed using a multi-taper method, due to its low variance (Thomson 1982). Following 
computation of the power spectra in each 30s time segment, the power in the θ- (3-7 Hz), α- (7-13 Hz), β- 
(13-32 Hz), γ- (48-100 Hz) and upper gamma (200-400Hz) bands will be computed. This will provide a 
feature matrix representing the sub-band power levels at different depths during resting state and 
changes during movement-related segments for each monopolar and bipolar contact. 
 
We will explore the dynamic LFP spectrum arising from each depth individually and investigate whether 
the depths related to increased β- (13-32 Hz) band power and other frequencies can be a predictor for 
the borders of the STN and optimal contacts used for DBS.   
 
We expect that abnormal brain activity will be characterized by a preferred correlation process, reflective 
of the structure of the local neural elements. Abnormalities in local neural elements or circuits may 
produce time series with distinct autocorrelation patterns, which can then be captured by autoregressive 
(AR) model parameters. In brief, the AR model represents the current observation by a linear combination 
of the past samples and a white-noise input (Hayes 2006). The data in each epoch are assumed to be 
stationary, as they originate from the same depth. Each epoch is analyzed with an AR model of order p. 
The model is, 
 , 
 
 
 
 
(1) 
where x is the output sequence, LFP data, a1,..p are the model parameters representing the weights of 
past samples, and 
 is the white noise.  
This method provides a great advantage over other techniques in describing the entire length of the data 
in each segment by a few “subject specific” model parameters, consequently resulting in a significant 
1
1
........
t
p t
p
t
t
x
a x
a x
e






te

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 22 of 35 
 
reduction in the dimensionality of the data analysis. At each contact, the model parameters will be 
estimated by using Burg’s Algorithm. The optimal model order will be selected based on the evaluation of 
three different criteria—i.e., Akaike Information Criterion (AIC), final prediction error (FPE), and minimum 
description length (MDL), as described previously (Hayes 2006).  
Once the AR model parameters have been estimated from the LFP data, these model parameters will be 
used along with subband powers as characteristic features for the prediction of STN location and 
stimulation settings. In addition, we will investigate whether the model parameters of different DBS 
contacts identified during rest and movement correlate with stimulation settings. We will explore different 
regression and classification techniques such as linear regression, linear discriminant analysis (LDA) and 
support vector machine (SVM) to estimate the predictive capability of the features extracted from LFP 
data. The estimation of the generalization capability of the developed models will be assessed by 
implementing a cross validation procedure with independent learning and testing sets. This will help to 
clarify the extent to which the stimulation correlates with actual LFP model parameters.  
7.1.1.2 
Sample Size Determination 
 
Performance of a power calculation is not relevant to the type of study proposed. Our previous studies 
demonstrate heterogeneity in the LFP patterns of PD subjects. The reasons for these differences are not 
well understood. Accordingly, we have designed this project as a pilot project to demonstrate the 
feasibility of the approach to analyzing spatiospectral LFP patterns using a segmented electrode and 
exploring the relationships to clinical outcomes. A sample size of 8 was chosen to capture enough 
heterogeneity in order to develop a more detailed investigative protocol in the future with well-defined 
sample sizes based on the present observations.   
7.1.1.3 
Analysis Populations 
 
In this study we will explore the predictive capacity of LFPs recorded from STN. In total, 8 patients 
undergoing bilateral STN DBS will be enrolled for this investigation over a 1-year period. The current 
surgical case load at BCM supports this level of enrollment.  
 
7.1.1.4 
Missing Data 
 
No missing imputations will be performed. 
7.1.2 
Secondary [Safety/Effectiveness] Endpoint Hypothesis(es) 
Compare the therapeutic window for stimulation delivered through directional and conventional leads and 
determine if the spatiospectral LFP patterns correlate with the presence of stimulation side effects.   
 
Justification of Clinical Investigation Design 
This is a prospective, feasibility study to explore the predictive capacity of LFPs recorded from STN. The 
outcomes of this pilot project will establish the scientific basis for whether LFPs recorded from a 
segmented electrode can be used for clinical decision making and to fine tune stimulation parameters.  
 
Multiplicity 
All statistical tests will be conducted using a Type I error of 0.05, unless stated otherwise. Family-wise 
error will be adjusted accordingly. 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 23 of 35 
 
 
Overall Sample Size 
A sample size of 8 was chosen to capture enough heterogeneity in order to develop a more detailed 
investigative protocol in the future with well-defined sample sizes based on the present observations.   
 
Deviations from Statistical Plan 
If any deviations from the original statistical plan occur, such deviations will be documented in the clinical 
study report or statistical report containing the analysis results. 
 
8 
Risks and Benefits 
 
The risks associated with the medical device can be found in the Instructions for Use. The study does not 
require any additional procedures or assessments over the standard of care. There are no additional risks 
introduced to study subjects. 
 
Risks Associated with the Device Under Investigation 
8.1.1 
Anticipated Adverse Device Effects 
Deep brain stimulation potentially has the following adverse effects: 
Possible surgical complications. Surgical complications include, but are not limited to, the following: 
intracranial hemorrhage (which can lead to stroke, paralysis, or death); subcutaneous hemorrhage or 
seroma; hematoma; cerebrospinal fluid leakage or cerebrospinal fluid abnormality; brain contusion; 
infection or inflammation; antibiotic anaphylaxis; skin disorder; edema; persistent pain at surgery site or 
IPG site; erosion; brachial plexus injury (nerves to chest, shoulder and arm); postoperative pain, stress, or 
discomfort; neuropathy (nerve degeneration); hemiparesis (muscular weakness or partial paralysis on 
one side of body); ballism or hemiballism (uncontrollable movements on both or only one side of the 
body); confusion—transient, nocturnal or ongoing; cognitive impairment, including delirium, dementia, 
disorientation, psychosis and speech difficulties; aphasia; deep vein thrombosis; complications from 
anesthesia; phlebitis (vein inflammation); pulmonary embolism (sudden blood vessel obstruction); aborted 
procedures (air embolism, unable to find target, surgical complication, etc.); complications from unusual 
physiological variations in patients, including foreign body rejection phenomena; pneumonia, seizure or 
convulsions; paralysis (loss of motor function, inability to move); stroke and death.  
 
Possible deep brain stimulation complications. Deep brain stimulation complications 
include, but are not limited to, the following:  
 
Device-related complications  
- Undesirable changes in stimulation related to cellular changes in tissue around the electrodes, changes 
in the electrode position, loose electrical connections, or lead fracture  
- Loss of therapeutic benefit as a result of change in electrode positions, loose electrical connections, or 
lead or extension fracture  
- Initial jolt or tingling during stimulation; jolting or shocking sensations  
- Infection  
- Paresthesia  
- Lead fracture, migration, or dislodgement  
- Misplaced lead  
- Extension malfunction, fracture, or disconnect  
- Deep brain stimulation system failure or battery failure within the device  
- Deep brain stimulation system malfunction or dislodgement  
- Spontaneous turning on or off of the IPG  

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
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written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 24 of 35 
 
- Allergic or rejection response to implanted materials  
- Persistent pain, tightness, or redness at the incision sites or general pain  
- General erosion or local skin erosion over the IPG  
- Persistent pain, tightness, or discomfort around the implanted parts (e.g., along the extension path in the 
neck)  
- Impaired wound healing (e.g., incision site drainage) or abscess formation  
- Additional neurosurgical procedure to manage one of the above complications or to replace a 
malfunctioning component  
Stimulation-related complications or other complications  
- Worsening of motor impairment and Parkinson’s disease symptoms including dyskinesia, rigidity, 
akinesia or bradykinesia, myoclonus, motor fluctuations, abnormal gait or incoordination, ataxia, tremor, 
and dysphasia  
- Paresis, asthenia, hemiplegia, or hemiparesis  
- Dystonia  
- Sensory disturbance or impairment including neuropathy, neuralgia, sensory deficit, headache, 
and hearing and visual disturbance  
- Speech or language impairment including, aphasia, dysphagia, dysarthria, and hypophonia  
- Cognitive impairment including attention deficit, confusion, disorientation, abnormal thinking, 
hallucinations, amnesia, delusions, dementia, inability to act or make decisions, psychic akinesia, long 
term memory impairment, psychiatric disturbances, depression, irritability or fatigue, mania or 
hypomania, psychosis, aggression, emotional lability, sleep disturbance, anxiety, apathy, drowsiness, 
alteration of mentation, postural instability and disequilibrium  
- Restless leg syndrome  
- Supranuclear gaze palsy  
- Hypersexuality or increased libido  
- Decreased therapeutic response  
- Urinary incontinence or retention  
- Diarrhea or constipation  
- Cardiac dysfunction (e.g., hypotension, heart rate changes, or syncope)  
- Difficulty breathing  
- Increased salivation  
- Weight gain or loss  
- Eye disorder including eye apraxia or blepharospasm  
- Nausea or vomiting  
- Sweating  
- Fever  
- Hiccups  
- Cough  
- Cramps  
- Worsening existing medical conditions 
 
8.1.2 
Risks Associated with Clinical Investigation Assessments 
There are no study related additional risks expected within this study. 
 
Risk Control Measures 
There are no study related additional risks expected within this study. 
 
Possible interactions with concomitant treatments 
There are no possible interactions with concomitant treatments. 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
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written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 25 of 35 
 
 
Anticipated Benefits 
The Infinity™  system with the directional lead provides additional programming options not available in 
other market-approved systems.   
 
If patients agree to take part in this study, there may or may not be direct medical benefits to individual 
patient.  The scientific use of the data, which is gathered from this study, may help the researchers 
discover better ways of programming movement disorder patients and improving quality of life. 
 
Risk-to-Benefit Rationale 
There are no study related additional risks expected within this study. 
 
History of Device Modifications or Recall 
This is a newly approved device and no device modifications have been reported to date.  No device 
recalls have been issued concerning this product. 
9 
Requirements for Investigator Records and Reports 
 
Deviations from CIP 
A deviation is defined as an instance(s) of failure to follow, intentionally or unintentionally, the 
requirements of the CIP. The investigator should not deviate from the CIP. 
 
In some cases, failure to comply with the CIP may be considered failure to protect the rights, safety and 
well-being of subjects; such non-compliance exposes subjects to unreasonable risks. Examples: failure to 
adhere to the inclusion/exclusion criteria, failure to perform safety assessments intended to detect 
adverse events. Investigators should seek to minimize such risks by adhering to the CIP. 
 
The PI must maintain accurate, complete, and current records, including documents showing the date of 
and reason for each deviation from the CIP. Relevant information for each deviation will be documented 
as soon as possible on the applicable CRF. The site will submit the CRF to the Sponsor. 
 
The PI is required to adhere to local regulatory requirements for reporting deviations to IRB/EC. 
 
 
Safety Reporting 
Safety surveillance within this study and the safety reporting performed both by the investigator and 
Sponsor starts as soon as the procedure begins. This is defined as from the time the [dilator/device 
delivery system has been introduced into the body]. 
 
The safety surveillance and the safety reporting will continue until the last investigational visit has been 
performed, the subject is deceased, the subject/investigator concludes his participation into the clinical 
investigation or the subject withdrawal from the clinical investigation. 
 
All adverse event data including deaths and device deficiency data (if applicable) will be collected 
throughout the clinical investigation and will be reported to the Sponsor on a CRF. 
 
Adverse events will be monitored until they are adequately resolved or the subject has ended his/her 
participation in the trial, whichever comes first. The status of the subject’s condition should be 
documented at each visit. 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
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written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 26 of 35 
 
9.2.1 
Subject Death 
Subject deaths will be documented and reported to the Sponsor as soon as possible (but no later than 3 
business days) after becoming aware of the event via the applicable CRF. 
9.2.2 
Complaints 
During the study, the investigator will be responsible for reporting all complaints. A complaint is defined as 
any written, electronic or oral communication that alleges deficiencies related to the identity, quality, 
durability, reliability, safety, effectiveness or performance of a device after it is released for distribution. 
 
If the complaint involves an AE, the investigator must complete an AE CRF, including the information on 
the complaint and submit to Abbott as soon as possible.  
 
Should a subject death be caused by the Abbott device or the device contributed to the death, the 
investigator should complete a Form 3500A (MedWatch) and submit to Abbott and the FDA within 10 
days after becoming aware of the event. 
 
 
Source records 
Source documents will be created and maintained by the investigational site team throughout the clinical 
investigation. The data reported on the CRFs will be derived from, and be consistent with, these source 
documents, and any discrepancies will be explained in writing. 
 
Records Retention 
The Sponsor and the Principal Investigators will maintain the clinical investigation documents as required. 
Measures will be taken to prevent accidental or premature destruction of these documents. The Principal 
Investigator or the Sponsor may transfer custody of records to another person/party and document the 
transfer at the investigational site or the Sponsor’s facility, as appropriate. 
 
These documents must be retained by the investigational site for a period of 2 years after the conclusion 
of the clinical investigation and made available for monitoring or auditing by the Sponsor’s representative 
or representatives of the applicable regulatory agencies. 
 
All original source documents must be stored for the maximum time required by the regulations at the 
hospital, research institute, or practice in question. If original source documents can no longer be 
maintained at the site, the investigator will notify the Sponsor.  
10 Clinical Data Handling 
The Sponsor will be responsible for the data handling. The Sponsor and/or its affiliates will be responsible 
for compiling and submitting all required reports to governmental agencies. Data will be analyzed by the 
Sponsor and may be transferred to the Sponsor’s locations worldwide and/or any other worldwide 
regulatory authority in support of a market-approval application. 
 Protection of Personally Identifiable Information 
Abbott respects and protects personally identifiable information collected or maintained for this clinical 
investigation. The privacy of each subject and confidentiality of his/her information will be preserved in 
reports and when publishing any data. Confidentiality of data will be observed by all parties involved at all 
times throughout the clinical investigation. All data will be secured against unauthorized access. 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
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written consent of Abbott. 
86357_CIP Template_Rev_C 
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 Data Management Plan 
A Data Management Plan (DMP) will describe procedures used for data review, database cleaning, and 
issuing and resolving data queries. If appropriate, the DMP may be updated throughout the clinical 
investigation duration. All revisions will be tracked and document controlled. 
 
Subject data will be captured in a validated electronic data capture (EDC) system hosted by the Sponsor. 
 
CRF received data for the clinical investigation will be entered by trained Abbott personnel. An electronic 
audit trail will be used to track any subsequent changes of the entered data. 
 
 Document and Data Control 
10.3.1 Traceability of Documents and Data 
The investigator will ensure accuracy, completeness legibility and timeliness of the data reported to the 
Sponsor on the CRFs and in all required reports. 
10.3.2 Recording Data 
The CRFs will be signed and dated by the authorized site personnel. Any change or correction to data 
reported on a paper CRF will be dated, initialed and explained if necessary, and will not obscure the 
original entry. 
 
11 Monitoring 
It is the responsibility of the Sponsor to ensure the clinical investigation is conducted, recorded and 
reported according to the approved CIP, subsequent amendment(s), applicable regulations and guidance 
documents. 
 
Centralized monitoring will occur through routine internal data review. This monitoring is designed to 
identify missing and inconsistent data, data outliers, and potential CIP deviations that may be indicative of 
site non-compliance. On-site monitoring may occur at the discretion of the Sponsor. 
 
12 Compliance Statement 
 Statement of Compliance 
This clinical investigation will be conducted in compliance with the most current regional and local laws 
and regulations. Principles of Good Clinical Practice will be followed as based on the most current version 
of the World Medical Association (WMA) Declaration of Helsinki. 
 
The investigator will sign a Clinical Trial Agreement and agrees to be compliant with it. The investigator 
will not start enrolling subjects or requesting informed consent from any subject prior to obtaining IRB/EC 
approval and relevant Regulatory Authority approval, if applicable, and authorization from the Sponsor in 
writing for the clinical investigation. If additional requirements are imposed by the IRB/EC or relevant 
Regulatory Authority, those requirements will be followed. If any action is taken by an IRB/EC or a 
relevant Regulatory Authority with respect to the clinical investigation, that information will be forwarded to 
the Sponsor. 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
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written consent of Abbott. 
86357_CIP Template_Rev_C 
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 Quality Assurance Audits and Regulatory Inspections 
The investigator and/or delegate should contact the Sponsor immediately upon notification of a regulatory 
authority inspection at the site. A monitor or designee will assist the investigator and/or delegate in 
preparing for the audit. The Sponsor may perform quality assurance audits, as required. 
 
The Principal Investigator or institution will provide direct access to source data during and after the 
clinical investigation for monitoring, audits, IRB/EC review and regulatory authority inspections, as 
required. The Principal Investigator or institution will obtain permission for direct access to source 
documents from the subject, hospital administration and national regulatory authorities before starting the 
clinical investigation. 
 Repeated and Serious Non-Compliance 
In the event of repeated non-compliance or a one-time serious non-compliance, as determined by the 
Sponsor, a monitor or designee will attempt to secure compliance by one or more of the following actions: 
• 
Visiting the investigator, 
• 
Contacting the investigator by telephone, 
• 
Contacting the investigator in writing, 
• 
Retraining of the investigator. 
 
If an investigator is found to be repeatedly non-compliant with the signed agreement, the CIP or any other 
conditions of the clinical investigation, the Sponsor will either secure compliance or, at its sole discretion, 
terminate the investigator’s participation in the clinical investigation. In case of termination, the Sponsor 
will inform the responsible regulatory authority, as required, and ensure that the IRB/EC is notified, either 
by the Principal Investigator or by the Sponsor. 
13 Suspension or Premature Termination of the Clinical Investigation 
The Sponsor reserves the right to terminate the clinical investigation at any stage, with appropriate written 
notice to the investigators, IRB/ECs and relevant Regulatory authorities, if required.  
 
A Principal Investigator, IRB/EC or regulatory authority may suspend or prematurely terminate 
participation in a clinical investigation at the investigational sites for which they are responsible. The 
investigators will follow the requirements specified in the Clinical Trial Agreement.  
 
If suspicion of an unacceptable risk to subjects arises during the clinical investigation or when so 
instructed by the IRB/EC or regulatory authority, the Sponsor may suspend the clinical investigation while 
the risk is assessed. The Sponsor will terminate the clinical investigation if an unacceptable risk is 
confirmed. If the Sponsor completes an analysis of the reasons for the suspension, implements the 
necessary corrective actions, and decides to lift the temporary suspension, the Sponsor will inform the 
Principal Investigators, IRB/EC, or regulatory authority, where appropriate, of the rationale, providing 
them with the relevant data supporting this decision. Approval from the IRB/EC or regulatory authority, 
where appropriate, will be obtained before the clinical investigation resumes. If subjects have been 
informed of the suspension, the Principal Investigator or authorized designee will inform them of the 
reasons for resumption. 
 
If the Sponsor suspends or prematurely terminates the clinical investigation at an individual 
investigational site in the interest of safety, the Sponsor will inform all other Principal Investigators. 
 
If suspension or premature termination occurs, the Sponsor will remain responsible for providing 
resources to fulfill the obligations from the CIP and existing agreements for following up the subjects 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 29 of 35 
 
enrolled in the clinical investigation, and the Principal Investigator or authorized designee will promptly 
inform the enrolled subjects at his/her investigational site, if appropriate. 
14 Clinical Investigation Conclusion 
The clinical investigation will be concluded when: 
• 
The site is closed AND 
• 
The final report has been provided to the investigator or the Sponsor has provided formal 
documentation of clinical investigation closure. 
15 Publication Policy 
Publications or presentations of clinical investigation methods or results will adhere to Abbott’s publication 
policy, which is based on Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines. A copy of the policy will be provided upon request of the investigator. 
 
. 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 30 of 35 
 
Appendix A: CIP Revisions 
 
Procedure for CIP Amendments 
 
This CIP may be amended as appropriate by the Sponsor. Rationale will be included with each amended 
version in the revision history table below. The version number and date of amendments will be 
documented. 
 
The acknowledgement of the amended CIP by the Coordinating Investigator (if applicable) and the 
Principal Investigators will be collected on the signature pages. 
 
IRB/EC and relevant Regulatory Authorities, if applicable, will be notified of amendments to the CIP. 
 
Revision History 
Amendment 
Number 
Version 
Date 
Rationale 
Details 
Not 
Applicable 
VA 
ddMMMyyyy 
First release of CIP 
NA 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 31 of 35 
 
Appendix B: Definitions 
 
Non-study Specific Definitions 
 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device under clinical investigation. 
 
This definition includes events related to the investigational medical device or the comparator. 
This definition includes events related to the procedures involved. 
 
Serious Adverse Event (SAE) 
An adverse event that led to: 
• 
Death 
• 
A serious deterioration in the health of the subject, that either resulted in: 
o 
A life-threatening illness or injury OR 
o 
A permanent impairment to a body structure or a body function OR 
o 
An in-patient or prolonged hospitalization OR 
o 
A medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function OR 
• 
Fetal distress, fetal death or a congenital abnormality or birth defect 
 
A planned hospitalization for a pre-existing condition, or a procedure required by the CIP is not 
considered a serious adverse event. 
 
Adverse Device Effect (ADE) 
An adverse event related to the use of an investigational medical device. 
 
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical 
device. 
 
This definition includes any event resulting from the use error or from intentional misuse of the 
investigational medical device. 
 
Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event. 
 
Unanticipated Adverse Device Effect (UADE) 
As defined in 21 CFR §812.3, unanticipated adverse device effects (UADE) are defined as any serious 
adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, 
a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the CIP or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.   
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 32 of 35 
 
Anticipated Serious Adverse Device Effect (ASADE) 
A serious adverse device effect which by its nature, incidence, severity or outcome has been previously 
identified in the risk analysis report. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
A serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
 
Device Deficiency (DD) 
A Device Deficiency is defined as an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. Device deficiencies include malfunctions, use errors and 
inadequate labeling. 
 
Vulnerable Subject 
Vulnerable subject is defined as individual whose willingness to volunteer in a clinical investigation could 
be unduly influenced by the expectation, whether justified or not, of benefits associated with participation 
or of retaliatory response from senior members of a hierarchy in case of refusal to participate. 
EXAMPLE Individuals with lack of or loss of autonomy due to immaturity or through mental disability, 
persons in nursing homes, children, impoverished persons, subjects in emergency situations, ethnic 
minority groups, homeless persons, nomads, refugees, and those incapable of giving informed consent. 
Other vulnerable subjects include, for example, members of a group with a hierarchical structure such as 
university students, subordinate hospital and laboratory personnel, employees of the Sponsor, members 
of the armed forces, and persons kept in detention. 
 
 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 33 of 35 
 
Appendix C: Bibliography 
 
Brown P, Oliviero A, Mazzone P, Insola A, Tonali P, and DiLazzaro V. Dopamine dependency of 
oscillations between subthalamic nucleus and pallidum in Parkinson’s disease. J. Neurosci. 2001. 
21,1033–1038. 
Chen CC, Pogosyan A, Zrinzo LU, Tisch S, Limousin P, Ashkan K, Yousry T, Hariz MI and Brown P. 
Intra-operative recordings of local field potentials can help localize the subthalamic nucleus in Parkinson’s 
disease surgery. Experimental Neurology. 2006 Mar; 198(1):214-21. 
Defer GL, Widner H, Marié RM, Rémy P, Levivier M. Core assessment program for surgical interventional 
therapies in Parkinson's disease (CAPSIT-PD). Mov Disord. 1999 Jul;14(4):572-84. 
Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, Daniels C, Deutschlander A, 
Dillmann U, Eisner W, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. 
N.Engl.J.Med. 2006 Aug 31;355(9):896-908. 
Hayes MH. Statistical digital signal processing and modeling. New York, NY: John Wiley & Sons, Inc.; 
2006.408-12 p. 
Kuhn AA, Trottenberg T, Kivi A, Kupsch A, Schneider GH nd Brown,P. The relation ship between local 
field potential and neuronal discharge in the subthalamic nucleus of patients with Parkinson’sdisease. 
Exp.Neurol. 2005. 194, 212–220. 
Ince NF, Gupte A, Wichmann T, Ashe J, Henry T, Bebler M, Eberly L and Abosch A. Selection of optimal 
programming contacts based on local field potential recordings from subthalamic nucleus in patients with 
Parkinson's disease. Neurosurgery. 2010 Aug; 67(2):390-7. 
Mera T, Vitek JL, Alberts JL, and Giuffrida JP. Kinematic optimization of deep Brain stimulation across 
multiple motor symptoms in Parkinson’s disease. J. Neurosci.Methods; 2011. 198, 280–286. 
Okun MS, Tagliati M, Pourfar M, Fernandez HH, Rodriguez RL, Alterman RL, Foote KD. Management of 
referred deep brain stimulation failures: a retrospective analysis from 2 movement disorders centers. 
Arch.Neurol. 2005 Aug;62(8):1250-5. 
Richardson RM, Ostrem JL, Starr PA. Surgical repositioning of misplaced subthalamic electrodes in 
Parkinson's disease: location of effective and ineffective leads. Stereotact.Funct.Neurosurg. 
2009;87(5):297-303. 
Rouse AG, Stanslaski SR, Cong P, Jensen RM, Afshar P, Ullestad D, Gupta R, Molnar GF, Moran DW 
and Denison TJ. A chronic generalized bi-directional brain–machine interface, J. Neural Eng. 2011. 
Thomson DJ. Spectrum Estimation and Harmonic Analysis. Proceedings of the IEEE (Special issue on 
spectrum estimation), 70 (1982), pp. 1055. 
Williams D, Tijssen M, vanBruggen G, Bosch A, Insola A, DiLazzaro V, Mazzone P, Oliviero A, 
Quartarone A, Speelman H, and Brown P. Dopamine-dependent changes in the functional connectivity 
between basal ganglia and cerebral cortex in humans. Brain; 2002. 125, 1558–1569. 
Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell R, Scott R, Ives N, Rick C, Daniels J, Patel S, 
and Wheatley  K. Deep brain stimulation plus best medical therapy versus best medical therapy alone for 
advanced Parkinson’s disease (PD SURG trial):a randomised, open-label trial. Lancet Neurol. 2010. 9, 
581–591. 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 34 of 35 
 
Appendix E: Case Report Form 
 
Case report forms will be provided under separate cover. 
 
 

 
Study Document No: SJM-CIP-10219 Ver. A 
Study Name: INVENT 
 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
86357_CIP Template_Rev_C 
Page 35 of 35 
 
Appendix F: Informed Consent Form 
 
The informed consent form will be provided under separate cover.