Basic Assessment of Safety and Minimally Invasive Stimulation Via Injectrode
Phase: NA
Conditions: Chronic Lower Limb Pain
Sponsor: Neuronoff, Inc

Basic Assessment of Safety and Minimally invAsive sTimulation via Injectrode
(BASMATI)
Title:
BASMATI - Basic Assessment of Safety and Minimally invAsive
sTimulation via Injectrode.
Protocol number:
NCP-01
Device:
Neuronoff Basmati Injectrode
Sponsor:
Neuronoff, Inc.
11000 Cedar Rd, Ste 290
Cleveland, OH 44146
Sponsor Contact:
Shaher Ahmad
Shaher@neuronoff.com
269-903-5499
Investigator:
Amol Soin, MD
7076 Corporate Way
Dayton, OH 45458
drsoin@gmail.com
Study Sites:
The Ohio Pain Clinic
7076 Corporate Way  
Dayton, OH 45458
(937) 434-2226
Medical Monitor:
Kettering Health Network
Kettering Innovation Center
Mary Connelly, PHD
(937) 298-4331
Revision
Revision Date
Sections
Revised
Description
Person Issuing
Change
DCO#
A
20201012
All
Initial Release
Shaher Ahmad
0041
Confidentiality Statement
This document contains confidential information that is the property of Neuronoff.Inc. and is subject to all of the
restrictions on use and disclosure contained in the study contract to which this is appended. Do not copy, disclose,
circulate or use for benefit for any third party without written authorization from Neuronoff.Inc.
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Protocol Synopsis
Sponsor
Contact
Information
Neuronoff, Inc.
11000 Cedar Rd, Ste 290
Cleveland, OH 44146
Title of Trial
BASMATI - Basic Assessment of Safety and Minimally invAsive sTimulation
via Injectrode.
Objective
The objectives of this non-significant risk (NSR) study are to evaluate the
safety of the short term placement of the Basmati Injectrode for up to 28 days
and the efficacy of conducting electrical current to stimulate subcutaneous
nerves on the explant date just prior to explant.
Clinical
Hypothesis
The 28 day temporary placement of a Basmati Injectrode does not result in
unexpected levels of inflammation or encapsulation.
Investigational
Device
A proprietary bio-electronic medical device (Neuronoff Basmati Injectrode
Insert) which is capable of transmitting small electrical currents to stimulate
sensory nerves.
Study Device
description
The Basmati Injectrode is a gold wire coil formed into the shape of a grain of
rice of 10mm length by 4mm width by 2 mm height. This gold material is of
99.99% purity and used in predicate medical devices as lead or electrode
material in neuromodulation applications.
Comparative
Data
Histopathological report describing findings in rodents with sub-chronic and
chronic placement of the Injectrode (REC-020).
Study Design
and Scope
The proposed study is a prospective, single-center, single-arm, non-randomized
design. Up to 10 study subjects will be provided with the placement of an
Injectrode insert. The maximal placement duration will be 28 days. Subjects
selected to participate in the trial are healthy without any preexisting condition
indicated to be treated. Each subject will be followed during the trial period of
approximately 50 days, including the time for screening and post-explant
follow-up. The study will end when the last subject has completed the trial
period and exited. After exit from the clinical study, subjects will continue to
be followed by their physician per standard of care. All device and
procedure-related adverse events (AEs) and unanticipated problems (UPs) will
be collected and reported per the study protocol.
Planned
Enrollment
We plan to enroll and screen up to 20 study participants, of which up to 10
participants will be provided with a Basmati Injectrode Insert for the trial.
Primary Safety
Objective
Primary measures of device safety will include verification of the absence of
unexpected inflammation and minimization of excessive encapsulation around
the Injectrode as verified by cell staining and pathohistological analysis.
Secondary
Effectiveness
Objective
Secondary measures of device effectiveness will include impedance and
stimulation threshold measurements for subcutaneous nervous tissue.
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STUDY FLOWCHART
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Table of Contents
Page
PROTOCOL TITLE
I
PROTOCOL SYNOPSIS
II
FLOWCHART
III
TABLE OF CONTENTS
IV
LIST of ABBREVIATIONS AND DEFINITIONS
VI
INTRODUCTION
1
BACKGROUND AND RATIONALE
1
CURRENT TREATMENT APPROACHES AND SHORTCOMINGS THEREOF
1
CLINICAL NEED FOR A “LAST MILE CONNECTION” TO CONNECT TO A NERVE
2
RATIONALE FOR THE NON-SIGNIFICANT RISK CLASSIFICATION OF THIS STUDY
4
COMPARISON TO EARLIER STUDIES
5
STUDY PARTICIPANT SAFETY
6
PRE-CLINICAL DATA / SUMMARY OF PREVIOUS STUDIES
6
OBJECTIVES
7
PRIMARY OUTCOME MEASURES: SAFETY
8
SECONDARY OUTCOME MEASURES: INTERFACING EFFICACY
8
DEVICE
9
NEURONOFF BASMATI INJECTRODE INSERT
9
REGULATORY CLASSIFICATION
11
STUDY DESIGN
12
SCHEDULE OF EVENTS (SOE)
13
OUTCOMES
14
PRIMARY SAFETY OUTCOME MEASURES
14
SECONDARY SAFETY OUTCOME MEASURES
14
MINIMIZATION OF BIAS
15
INVESTIGATORS
16
INVESTIGATOR SELECTION AND RESPONSIBILITIES
16
STUDY POPULATION
17
INCLUSION CRITERIA
17
EXCLUSION CRITERIA
17
SAMPLE SIZE
18
METHODS AND PROCEDURE
19
DATA COLLECTION REQUIREMENTS
19
SUBJECT SCREENING PROCEDURE
19
INFORMED CONSENT
20
SCREENING AND ENROLLMENT VISIT (IN-PERSON, DAY -5 OR DAY -4)
20
ALLERGY TEST PATCH REMOVAL VISIT (CALL, DAY -2)
20
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INSERT PLACEMENT VISIT (IN-PERSON, DAY 0)
21
FOLLOW-UP VISITS (IN-PERSON OR CALL, DAY 7 AND DAY 14)
23
EFFICACY & EXPLANT VISIT (IN-PERSON, DAY 28)
24
POST-EXPLANT VISIT & STUDY EXIT (IN-PERSON, DAY 42 +/- 2)
31
ADVERSE EVENT REPORTING
32
ADVERSE EVENTS
32
ANTICIPATED ADVERSE DEVICE EFFECTS
32
UNANTICIPATED ADVERSE DEVICE EFFECTS
33
STATISTICS
35
STUDY POPULATION
35
OBSERVATIONAL PILOT STUDY
35
ETHICS
36
MEDICAL ETHICS COMMITTEE ( IRB ) REVIEW
36
ETHICAL CONDUCT OF THE STUDY
36
STUDY PARTICIPANT INFORMATION AND CONSENT
36
STUDY ADMINISTRATION
37
STUDY INITIATION
37
CLINICAL SUPPLIES
37
CASE REPORT FORMS (CRFS)
37
STUDY COMPLETION
38
FINAL REPORT
38
RETENTION OF STUDY RECORDS
38
CONFIDENTIALITY
38
PUBLICATION OF STUDY RESULTS
38
SIGNATURE OF PRINCIPAL INVESTIGATOR
39
DECLARATION OF HELSINKI
40
REFERENCES, REGULATIONS AND STANDARDS
44
REFERENCES
44
FDA GUIDANCE ON GOOD CLINICAL REGULATIONS FOR MEDICAL DEVICE STUDIES
45
ISO STANDARDS
45
APPENDIX 1: FIGURES AND TABLES
46
FIGURES
46
TABLES
46
APPENDIX 2: INCLUDED DOCUMENTS & COMPONENTS LIST
47
LIST OF INCLUDED DOCUMENTS
47
LIST OF ASSEMBLY AND COMPONENT PARTS
47
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List of Abbreviations and Definitions
Abbreviation/Term
Definition
ADE:
Adverse Device Event
AE:
Adverse Event
CE:
Conformité Européenne (European Conformity)
CIP:
Clinical Investigational Plan
CRF:
Case Report Form
CTA:
Clinical Trial Agreement
EC:
Ethics Committee
FDA:
United States Food and Drug Administration
GCP:
Good Clinical Practices
ICF:
Informed Consent Form
ICH:
International Conference on Harmonization
ID:
Identification
IRB:
Institutional Review Board
ISO:
International Organization for Standardization
kHz:
Kilohertz
NRS:
Numeric Rating Scale
PW:
Pulse Width
SADE:
Serious Adverse Device Event
SAE:
Serious Adverse Event
SCS:
Spinal Cord Stimulation
SOC:
Standard of Care
UADE:
Unanticipated Adverse Device Effect
USADE:
Unanticipated Serious Adverse Device Effect
UP:
Unanticipated Problem
µsec:
MicroSecond
µA:
Micro Ampere
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1.0
INTRODUCTION
1.1
Background and rationale
Neuromodulation, sometimes referred to as Bioelectronic Medicine, is using electrical stimulation or
blocking of neural activity to achieve beneficial effects in the human body. These effects can include
the reduction of chronic pain, reducing the frequency of overactive bladder, epileptic events, up to a
modulation of the metabolic activity of inner organs. In many cases, afferent and efferent nerves of
interest for interfacing are located within 5 cm when measured from the surface of the skin.
Unfortunately, extracorporeal means of modulating neural activity in these nerves cannot be achieved
reliably by widely available technologies such as Transcutaneous Electrical Nerve Stimulation (TENS)
as the electric field applied on the outside of the skin only penetrates a few millimeters into the body
before current densities have dissipated enough to limit the ability to reliably activate or deactivate
neural tissue.
In order to electrically interface with these nerves, the clinical standard today is to place an implantable
pulse form generator (IPG) into the patient, followed by one or more electrodes connecting the IPG to
the nerve of interest by means of an open cut-down procedure. This often requires general anesthesia, a
surgeon to place the devices, and commonly results in significant scarring visible post surgery as well
as a large burden on the payer in the healthcare system for the cost of the extensive procedure.
1.2
Current treatment approaches and shortcomings thereof
Today, individuals suffering from chronic intractable pain of the trunk and/or limbs are typically
treated on a continuum with less invasive therapies prescribed first. Established, non-surgical treatment
options include, but are not limited to, oral medications including opioid-based drugs, physical therapy,
TENS, acupuncture, nerve blocks, radiofrequency ablation and other options based on clinical
judgment. The surgical treatment options for these study participants include surgery of the spine,
sympathectomy, intrathecal drug pumps, and spinal cord stimulation (SCS) systems .
1
Neuromodulation offers many treatment solutions to pathologies such as Parkinson’s Disease,
peripheral nerve pain, overactive bladder (OAB) and neuralgia among others. Current solutions are
divided between invasive, minimally invasive and non-invasive treatments and each come with their
own set of challenges and benefits. Invasive treatments generally require surgery under anesthesia to
place signal generators, leads and electrodes, often resulting in visible scars and are the most expensive
treatment option. Non-invasive treatments typically have the least efficacy, reliability problems,
limited applicability to a few locations and no ability to block nerves. Only few invasive treatments
exist and those generally require a bulky external signal generator, and often don’t provide the option
to place an electrode as a cuff around a nerve, a necessary requirement for optimal mechanical and
electrical interfacing for the long term. For many potential applications that could be treated with
1 American Chronic Pain Association Resource Guide to Chronic Pain Medication and Treatment, 2014 Edition.
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neuromodulation technology, nerves of interest are located deeper than 5 mm when measured from the
surface of the skin. This limitation of non-invasive TENS technology to nerves only very close to the
skin is greatly holding back the development of novel treatments using neuromodulation.
There is a need for a technology that conducts an externally generated signal to a nerve of interest to
locations from just beneath the skin to a target nerve at a depth of up to 5cm.
1.3
Clinical need for a “last mile connection” to connect to a nerve
The future of neuromodulation is expected to become more patient centric and will focus on various
unserved needs patients have today. One of these needs is to be free from the need to undergo revision
surgeries every 3 to 7 years to replace an exhausted battery by explanting an old neuromodulation
device and reimplanting a new one in its place. In addition, a second need is to minimize the
prevalence and size of scars caused by the surgery to place first an electrode on a nerve target and
second the scar caused by the placement of the signal generator.
Neuronoff, Inc. set out to provide a solution to both of these needs by electrically connecting the nerve
with an insert that can be delivered via needle puncture to minimize scarring . The insert functions as
2
an electrical conduit (coupler), transferring current applied to the skin (e.g. via TENS) via a very low
impedance down to the nerve of interest (figure 1). In essence, this conduit provides the last mile
connection for electrical signals from the skin to the target nerve.
Figure 1: Comparison between the Target Product (A-C) and the BASMATI Injectrode insert (D). While electrical energy
applied by a TENS unit does only reach approximately 3 to 5 mm deep (A), a low impedance conduit (B) can conduct
electrical energy to a location more distant inside the body to activate a nerve (C). The BASMATI insert is manufactured
following similar procedures and from the same materials as the expected Target product, thus providing an assessment of the
safety (primary objective assessed in this study) and interfacing efficacy (secondary objective) of the technology.
2 Trevathan JK, Baumgart I, Nicolai EN, et al. A Truly Injectable Neural Stimulation Electrode Made From an In-Body Curing
Polymer/Metal Composite. BioRxiv. 2019 BioRxiv https://doi.org/10.1101/584995.
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Preclinical animal and benchtop work has been successfully conducted to prove out the technology.
The conduit placement is designed to be very similar to a lidocaine injection pain physicians provide
as part of their daily practice today, utilizing fluoroscopic or ultrasound visualization during the
procedure. Using a needle of 2 to 5 mm diameter as a trocar, a wire rope is inserted to be in close
proximity to the nerve at one end of the conduit, while the other (“current collector”) end is left as a
loop in the subcutaneous tissue. After closing the puncture wound with steri strips or sutures, the
patient will be allowed to recover for a few days, allowing the injected conduit to stabilize. After a few
days of recovery, electrical current to stimulate the nerve is applied on the outside of the skin with a
TENS unit, from where it reaches the collector end just below the skin. Once the current reaches the
collector end, it is transferred at a very low electrical impedance to the nerve target, providing the
neuromodulation treatment.
The advantages of this solution are (1) that the signal generator is outside the body, eliminating the
need for battery replacement surgeries and (2) that the puncture wound to place the conduit leaves a
significantly smaller scar than current procedures to place neuromodulation electrodes, leads and
signal generators.
This conduit represents an injectable electrode that is formed into its final shape inside the body, or
Injectrode for short.
While Neuronoff, Inc. has tested all components of this system in preclinical benchtop and animal
studies, including very successful long term biocompatibility studies of the actual Injectrode insert for
up to 180 days, it was deemed to be in the best interest of study participants and the company to
conduct the clinical work in two subsequent clinical studies that build on top of each other:
First a clinical study to document the safety and electrical interfacing efficacy of the Injectrode insert
for up to 28 days. This early feasibility study focuses primarily on documenting biocompatibility by
having the Injectrode insert placed just below the skin into the subcutaneous tissue. Based on extensive
chronic work in animals a rejection reaction is not expected, but if it were to happen, would be very
easily dealt with by explanting the small insert. After 28 days, a short electrical measurement would be
used to confirm successful interfacing with the device just minutes prior to removal by a dermatologic
surgeon. This study design allows for risk to be very minimal, enabling the NSR designation for this
study. The document in hand describes this first study.
The second clinical study is designed to build on the knowledge of the successful first study and will
evaluate the deployment of a longer version of the Injectrode insert from a subcutaneous location to a
nerve at a depth of approximately one inch in depth measured from the skin. The second study thus
represents an actual treatment efficacy study for a clinical condition. This second clinical study is a
future study and not the one described in the document in hand.
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1.4
Rationale for the non-significant risk classification of this study
While interfacing with a nerve at a depth of 2 to 3 cm would be a possibility for an early feasibility
study, it was determined that a subcutaneous placement of the shortened study device would provide
the same biocompatibility data and the same electrical transmission capabilities efficacy data, while
subjecting the study participants to a very minimal and controlled amount of Non-Significant Risk
(NSR).
Under 21 CFR 812.3(m), an NSR device study is one that does *not* meet the definition for an
SR device study. Below we cover all criteria that define an SR device and then detail why the
Basmati Injectrode does *not* meet these.
Specifically, as per 21 CFR 812.3(m), an SR device:
1.
Is intended as an implant and presents a potential serious risk to the health, safety, or
welfare of a subject.
The commercial version of Neurnoff’s Injectrode will be an implantable electrode. However,
this early feasibility prototype is limited to 28 days of use to avoid risk resulting from
long-term implantation duration where regular follow-up is impractical or impossible.
Therefore, the Basmati insert does not meet the definition of an implant. In this study, the
Basmati will be used to document the clinical biological response after a placement duration of
28 days only.
According to FDA guidance, “Use of International Standard ISO 10993,
“Biological Evaluation of Medical Devices Part 1: Evaluation and Testing” (2013): a device
that makes contact with tissue for a period of time less than 30 days poses considerably lower
risk to patients.
2.
Is purported or represented to be for use supporting or sustaining human life and
presents a potential for serious risk to the health, safety, or welfare of a subject.
The Basmati Injectrode insert is not intended for use supporting or sustaining human life. In
the proposed safety study, the device will be temporarily implanted subcutaneously for the
purpose of confirming its biocompatibility compared to a previous animal study.
3.
Is for a use of substantial importance in diagnosing, curing, mitigating, or treating
disease, or otherwise preventing impairment of human health and presents a potential
for serious risk to the health, safety, or welfare of a subject.
In the proposed safety study, the Basmati insert will be used as a passive device not intended
for diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of
human health. Prior to removing the device in a minimally invasive procedure, the Injectrode
will be briefly interfaced with electrical current using standard electro-acupuncture techniques,
following the labeling for these approved devices. The total time of exposure to this limited
stimulation period will be approximately 20 minutes right prior to device extraction via Mohs
procedure.
4.
Otherwise presents a potential for serious risk to the health, safety, or welfare of a
subject.
Based on the Neuronoff, Inc. Quality Management System, risks associated with the device
will be evaluated and addressed per the Design Control Procedure, SOP-02 and the Risk
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Management Procedure, SOP-05 and according with
the ISO-14971 Risk Management
Standard to assure that the Basmati Injectrode insert is deemed to not represent any potential
for serious risk to the health, safety, or welfare of a subject. The minimally invasive placement
at a location in the subcutaneous tissue and rigorous follow-up schedule are designed to allow
the physician to monitor the response of each study participant very closely and, if necessary,
explant the device prior to the 28 day mark without unnecessary risk to the health, safety, or
welfare of a subject. The material of the Injectrode is 99.99% gold, a material commonly used
in neuromodulation electrodes that is bioinert and very well received by humans clinically.
The method of removing the Injectrode at the end of the safety study will follow a procedure
similar to a Mohs procedure, a standard clinical practice that poses little risk to study subjects.
Subjects will be followed for signs of inflammation of the surgical site, granulomas, irritation.
This early feasibility study aims to document the clinical biological response to an Injectrode, roughly
the size of a Basmati rice grain, placed temporarily into up to 10 healthy volunteers for a duration of
up to 28 days. The efficacy of the device is assessed by measuring electrical and sensory nerve
recruitment data immediately prior to explanting the device. These data are intended to provide
rationale for a follow-up study testing a therapeutic intervention.
Risk to the study participant is further minimized by placing the study device subcutaneously with the
option for a quick minimally invasive explant procedure before the 28 day mark if deemed necessary
by the study PI.
This non-significant risk (NSR) study is the first of two early feasibility studies. This first NSR study
is designed to subject the study participants to a minimal risk while collecting first human
biocompatibility, electrical interface and neurostimulation data.
The expected data set is designed to enable a follow-up study investigating the placement of a longer
Basmati-style Injectrode that ranges from the subcutaneous tissue to a nerve located at an approximate
depth of 2 to 3 cm deep inside the body. The present BASMATI study mimics the placement into the
subcutaneous tissue location and thereby provides the data to enable the follow-up study evaluating a
longer Basmati-like electrode to be placed. To minimize risk for participants in the mentioned
follow-up study, biocompatibility data and electrical interfacing data are collected in the first NSR
study as described in the document in hand.
1.5
Comparison to earlier studies
The Basmati Injectrode will be placed subcutaneously in up to 10 healthy volunteers for a duration of
up to 28 days. On the last day of the study, the Basmati Injectrode will be explanted with a margin of
approximately 1mm of healthy tissue utilizing a Mohs surgical approach, ensuring maximal study
participant safety while enabling the collection of histological samples for chronic human
biocompatibility data. Just prior to explanting the device, two very small 30 gauge needles (similar to
electro-acupuncture needles) will be placed approximately 5mm into the skin at the location of the
subcutaneously placed Basmati, thereby forming an electrical interface with the Basmati. Electrical
impedance and stimulation thresholds for subcutaneous afferences (sensory nerves) will be recorded
with the two needles and a TENS electrode patch placed extracorporeally at a distance of
approximately 10 cm from the Basmati location.
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This approach is similar to that utilized with the StimRouter Neuromodulation System, which also
consists of an implanted lead with external stimulation equipment to activate the lead transcutaneously
. Both systems utilize minimally invasive implantation techniques, with the probe injected via
3 4 5
hollow stainless steel tubes
. However, the Injectrode is different in that it is presented as a gold mesh
6 7
as opposed to a fixed metal coil, which allows for improved in-body conforming and thus better reach
of potentially hard-to-access anatomic targets. Also, in the least invasive use case, the Injectrode can
be stimulated via an external TENS unit without requiring an implanted stimulation cable. Thus, the
Injectrode offers improved placement potential and functionality with similar or lesser invasiveness
than available technologies.
1.6
Study participant safety
Subject safety is our main priority. Accordingly, the devices chosen for this study were selected for
their ability to minimize risk. Stimulation will be controlled using an FDA cleared Constant Current
Stimulator (DS7A, Digitimer, USA). Impedance will be measured with a handheld, battery-powered
oscilloscope (ScopeMeter, Fluke, USA) that is certified and calibrated. Percutaneous interfacing with
the Injectrode will be achieved using standard clinical grade sterile 30 gauge needles.
1.7
Pre-clinical data / Summary of previous animal studies
Basmati style Injectrodes, in various sizes and shapes (ranging from 8x1x1mm to 12x5x2mm) have
been placed successfully subcutaneously in 54 rodents (n=108 devices), for varying durations up to
180 days. No serious adverse events have occured. As such, a strong safety profile for the device,
sterilization method, placement location, and biological response has been demonstrated. Percutaneous
conductivity was also measured in these animals throughout the course of the device placement period.
Surgical removal of the device in a survival procedure (4 weeks placed, removed, 4-8 weeks survival
post removal) has also been completed for n=8 devices, also without any adverse events.
In a subset of the 108 devices, removal of the device was completed with the skin layer left intact,
intended for histopathological analysis to assess the biological response to the device. A representative
sample (n=30) was submitted to a third-party histopathologist (Nicholas P. Ziats, Case Western
Reserve University). Two transverse sections of the subcutaneously placed devices were stained with
either H&E and Trichrome, for placement periods of 4 (n=12), 8 (n=12), 12 (n=2), and 26 weeks (180
7 Bioness® StimRouter™Neuromodulation System for Chronic Pain Therapy. First Posted May 7, 2012.
https://clinicaltrials.gov/ct2/show/NCT01592344?id=NCT00665132+OR+NCT01592344&draw=2&rank=1&load=cart
6 Acute Human Study: StimRouter for Peripheral Nerve Stimulation of Discrete Peripheral Nerves (SimRouter). First Posted April 23, 2008.
https://clinicaltrials.gov/ct2/show/NCT00665132?id=NCT00665132+OR+NCT01592344&draw=2&rank=2&load=cart
5 Deer T, Pope J, Benyamin R, Vallejo R, Friedman A, Caraway D, Staats P, Grigsby E, McRoberts WP, McJunkin T, Shubin R, Vahedifar P,
Tavanaiepour D, Levy R, Kapural L, Medhail N. Prospective, Multicenter, Randomized, Double-Blinded, Partial Crossover Study to Assess
the Safety and Efficacy of the Novel Neuromodulation System in the Treatment of Patients With Chronic Pain of Peripheral Nerve Origin.
Neuromodulation. 2016 Jan;19(1):91-100: https://doi.org/10.1111/ner.12381
4 Deer TR, Pope JE, Kaplan M. A novel method of neurostimulation of the peripheral nervous system: The StimRouter implantable device.
Tech Reg Anes Pain Manag. 2012 Apr;16(2):113-117. https://doi.org/10.1053/j.trap.2013.02.007
3 Deer TR, Levy RM, Rosenfeld EL. Prospective Clinical Study of a New Implantable Peripheral Nerve Stimulation Device to Treat Chronic
Pain. Clin J Pain. 2010 Jun;26(5):359-72. https://doi.org/10.1097/AJP.0b013e3181d4d646
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days, n=4). The complete histopathological report is included in the appendix (REC-020). The
histopathologist drew the following conclusions:
There was normal fibrous capsule formation, with the most prominent finding being the expected
inflammatory response to any implanted material. The fibrotic response was variable – some devices
had a higher degree of inflammatory and foreign body giant cells than others. Responses range from
+1 to +3 (mild to moderate) responses, the histopathologist stating that this range did not seem
concerning and that he assumed it to simply be inter-subject variability. He cited the variable response
of patients to COVID as a case-in-point. There was no evidence of adverse granuloma, necrosis (e.g.,
no acute toxicity), tumor formation or infection. More details are provided in the complete
histopathological report that is included in the appendix (REC-020).
Below is a representative histological image (Trichrome Stained), identifying the fibrous capsule and
small vasculature with red blood cells (RBCs). The small blood vessels are indicative of a well
received implant with a thin fibrous capsule. The gold wires of the Basmati Injectrode are also pointed
out, with an image of higher magnification showing the individual RBCs within the vascular lumen,
along with collagen fibers - indicative of stable integration and a normal fibrotic response.
Figure 2: Representative histological image of a cross-section of the gold wires of an Basmati style Injectrode indicating key
histological features (Fibrous Capsule, Vasculature - Lumen and Red Blood Cells). A higher magnification insert to the right
shows a blood vessel lumen and RBS’s, indicative of a readily integrated device.
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2.0
OBJECTIVES
Success of this study is defined based on primary and secondary outcome measures. These are
provided with greater detail below.
2.1
Primary Outcome Measures: Safety
Primary measures focus on device safety and will include the verification of the absence of unexpected
inflammation and minimization of excessive encapsulation around the Injectrode as verified by cell
staining and pathohistological analysis. Fluoroscopic imaging will be used to document positioning of
the Basmati Injectrode lead.
2.2
Secondary Outcome Measures: Interfacing Efficacy
Secondary measures focus on device effectiveness. These will include impedance and stimulation
threshold measurements for subcutaneous afferent nervous tissue.
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3.0
DEVICE
3.1
Neuronoff Basmati Injectrode insert
This Clinical Non-Significant Risk (NSR) Study will focus on the placement, interfacing with and
histopathological assessment of the Basmati Injectrode.
The Basmati Injectrode insert (figure 3) is a mesh formed from gold wire of 99.99% purity, a widely
used material in medical devices, offering excellent biocompatibility combined with chemical,
mechanical and electrical longevity when implanted into the human body
. The conductive mesh
8 9 10 11
is fabricated from wire with a nominal diameter of 25 microns and at a size of 4 mm width by 10 mm
length at about 1.75 mm thickness. This size is similar to a cooked grain of basmati rice.
Figure 3: Basmati Injectrode insert is about the size of a grain of rice.
11 Product: Gold Eyelid Weight Implants, Composed of 99.99% Gold
https://www.accessdata.fda.gov/cdrh_docs/pdf/K971242.pdf
https://www.accessdata.fda.gov/cdrh_docs/pdf15/K150986.pdf
10 Product: Soft Tissue Marker, Composed of 99.95% Gold
https://www.accessdata.fda.gov/cdrh_docs/pdf3/k031206.pdf
https://www.accessdata.fda.gov/cdrh_docs/pdf9/K091645.pdf
9 Hielm-Bjorkman A, Raekallio M, Kuusela E, Saarto E, Markkola A, Tulamo RM. Double-blind evaluation of implants of gold wire at
acupuncture points in the dog as a treatment for osteoarthritis induced by hip dysplasia. Vet Rec. 2001;149(15):452-456.
https://doi.org/10.1136/vr.149.15.452
8 Geddes, L.A., Roeder, R. Criteria for the Selection of Materials for Implanted Electrodes. Annals of Biomedical Engineering 31, 879–890
(2003). https://doi.org/10.1114/1.1581292
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The Basmati Injectrode insert will be provided, loaded inside a delivery system to be attached to a
standard 3mL luer lock Syringe. The Basmati Injectrode System Assembly (F-0001, see Figure 5A and
5B) is made of materials and components that are FDA listed from qualified suppliers, and will have
limited duration of contact with study participant tissue. The materials along with all other
device-contacting manufacturing materials are easily cleaned and sterilized following validated
processes.
The device assembly will be delivered clean, and sealed in a Steam sterilization tyvek
pouch placed in a padded box with the appropriate labels.
The device will be sterilized using a
recommended and validated steam sterilization cycle. The Basmati Injectrode will be placed into the
body by a cannula-based delivery device following a stab incision. Removal of the retaining clip
(C-0002) readies the device for injection from the cannula (C-0001) into the surgical site.
Figure 4: Basmati Injectrode System Assembly in a sterilization pouch (without label)
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During the surgical procedure, the Basmati Injectrode is ejected from the delivery device after
introducing the cannula into a subcutaneous tunnel first created by blunt dissection. Creating the skin
opening with sharps, a channel via blunt dissection and deploying the Basmati Injectrode is a
procedure that can be achieved in under 10 minutes of surgical time.
Figure 5: Delivery device attached to a standard 3mL syringe (A) and the Basmati Injectrode ejected from the delivery device
(B)
The Basmati InjectrodeTM is indicated for the investigational use for the assessment of chronic
biocompatibility, electrical interfacing and neurostimulation data in humans. The investigational
devices used for this study will be sourced from Neuronoff, Inc. and a list of all components is
provided in the appendix.
3.2
Regulatory Classification
The Neuronoff, Inc Basmati InjectrodeTM is an investigational device and is not yet classified.
However, similar devices (i.e. StimRouter) are identified as Class II by the US FDA.
The sponsor has determined that this qualifies as an early feasibility study of non-significant risk.
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4.0
STUDY DESIGN
The proposed study is a prospective, single-center, single-arm, non-randomized design. The study will
screen up to 20 subjects for study eligibility and potential enrollment. Up to 10 study participants will
be provided with the placement of a Basmati Injectrode insert. The maximal placement duration will
be 28 days. Subjects selected to participate in the trial will be solely healthy volunteers without any
preexisting condition indicated for treatment. Each subject will be followed during the trial period of
approximately 45+/-2 days.
The study will end when the last subject has completed the trial period and exited. The expected
enrollment period for this study is approximately 2 months. After exit from the clinical study, subjects
will continue to be followed by their physician per standard of care. All device and procedure-related
AEs and UPs will be collected and reported per the study protocol.
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4.1
Schedule of Events (SOE)
Assessments and Data Collection
Screening
and
Enrollment
Call for
patch
removal
Injectrode
Placement
Follow-
up visits
Efficacy and
Explant visit
Post study
follow-up
Day (relative vs. Placement)
-5 to -4
-2
0
7 ± 2
14 ± 2
28 (-2 to 0)
48 ± 2
●
Eligibility confirmation
✓
●
Medical history
●
Physical exam
✓
✓
●
Informed consent
✓
●
Record demographics
●
Verification of absence of allergy
to gold & pregnancy test
●
Confirmation of study eligibility
✓
✓
✓
●
Gold skin patch test placement
✓
●
Removal of skin patch
✓
●
Read skin test patch results
✓
●
Basmati placement procedure
●
Ultrasound & Fluoroscopy image
capture
✓
✓
✓
(pre & post)
(✓)
●
Recording of images of surgical
site / placement location
●
Remove skin suture(s) if placed
during surgery
✓
✓(post)
✓
(✓)
✓
✓
(✓)
●
Measure
impedance
needle
to
needle connection
●
Measure stimulation thresholds
●
Removal procedure
●
Study participant exit
✓
✓
✓
✓
Table 1: Assessments and data collection
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5.0
OUTCOMES
The outcomes of the study are focused on collecting data to determine clinical outcomes of placing the
Basmati Injectrode for up to 28 days in healthy study participants to 1) assess tissue responses and, on
the last day just prior to explant, 2) collect data describing the quality of the electrical interfacing with
the Injectrode from outside of the body, as well as with subcutaneous sensory nerves surrounding the
Injectrode insert.
Safety data will also be collected at all visits. Data will be collected using:
●
True color images of the surgical site and the insert placement location.
●
Ultrasound and fluoroscopy (x-ray) images of the insert placement location.
●
CRFs to capture any pain or discomfort, AEs and UPs.
●
Patho-histological data from tissue samples collected during the explant procedure (Injectrode
with approximately 0.5 to 1mm of naïve tissue in Mohs style procedure).
5.1
PRIMARY SAFETY OUTCOME MEASURES
Primary measures of device safety will include verification of the absence of unexpected inflammation
and minimization of excessive encapsulation around the Injectrode as verified by cell staining and
pathohistological analysis. Fluoroscopic imaging will be used to document positioning of the Basmati
Injectrode lead.
5.2
SECONDARY SAFETY OUTCOME MEASURES
Secondary measures of device effectiveness will include impedance and stimulation threshold
measurements for subcutaneous nervous tissue.
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6.0
MINIMIZATION OF BIAS
Potential sources of bias in this study may result from selection of subjects, and evaluation of study
data. The following methods have been incorporated into the study to minimize potential bias:
Subjects will be screened to confirm eligibility for enrollment with defined inclusion/exclusion criteria
prior to enrollment. Subject demographics will be collected at baseline on possible differences that
may affect the primary objective. All study clinicians, participating site personnel, and the Sponsor’s
personnel will be trained on their respective aspects of the study using standardized training materials.
All study clinicians will be trained on and required to follow the Clinical Investigation Plan.
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7.0
INVESTIGATORS
7.1
INVESTIGATOR SELECTION AND RESPONSIBILITIES
In order for the Investigators to participate in the study, they must provide a Curriculum Vitae
(CV) demonstrating evidence of sufficient training and experience in the management of study
participants with chronic pain. The Investigator’s participation in other clinical studies must not
present a conflict of interest and will not interfere with the clinical study enrollment, study
management or study confidentiality. Each participant must be willing to provide any conflicts of
interest details, and must be willing to comply with all federal laws and regulations as well as IRB
rules regarding clinical studies.
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8.0
STUDY POPULATION
The study will recruit healthy volunteers that pass a thorough general medical exam. Subjects may
either be male or female and must meet all of the study's eligibility criteria, which are typical eligibility
criteria for early feasibility studies. They will be required to sign an informed consent form prior to
being asked to participate in the study, undergoing any study-related procedures or having any data
collected. It is expected that up to 20 subjects may be screened to be enrolled based on eligibility, and
up to 10 subjects will undergo minimally invasive surgery to implant the Basmati Injectrode.
8.1
Inclusion Criteria
To be eligible for this study, study participants MUST:
1.
Sign a valid, Institutional Review Board (IRB)-approved informed consent form (ICF) and
understand the study requirements.
2.
Be 18 years of age or older when written informed consent is obtained.
3.
Be in good physical and mental health as assessed by a general practitioner.
4.
Be able to tolerate electrical stimulation (TENS).
5.
Be willing and able to understand and comply with all study-related procedures during the
course of the study.
8.2
Exclusion Criteria
To be eligible for this study, study participants MUST NOT:
1.
Have a cognitive impairment or exhibit any characteristic that would limit the study
candidate's ability to completely understand and sign a valid, IRB-approved informed consent
form.
2.
Have a positive pregnancy test (conducted during enrollment).
3.
Have a positive Allergic reactivity to Gold skin test (conducted during enrollment).
4.
Show symptoms indicative for Covid19 as assessed during enrollment.
5.
Have a skin condition at the planned surgical location.
6.
Have a blood coagulation disorder or other indication with the potential to impact the study
biocompatibility data in unpredictable ways.
7.
Have a medical condition that is a contraindication for minimally invasive surgery.
8.
Be implanted with a cardiac defibrillator or pump.
9.
Have a history of cardiac arrhythmia with hemodynamic instability
10. Be implanted with a neurostimulator.
11. Have any active electrical implant of any other kind.
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12. Have metal implants (particularly in hip).
13. Have active infection.
14. Have allodynia.
15. Take regular use of antiplatelet medications (e.g. aspirin, ticlopidine (Ticlid), clopidogrel
(Plavix), tirofiban (Aggrastat) or eptifibatide (Integrilin)).
16. Have untreated drug habituation or dependence.
17. Have uncontrolled seizures (averaging > 2 seizures per month).
18. Currently require, or be likely to require, diathermy and/or MRI during study duration.
19. Have a history of adverse reactions to local anesthetics (e.g. lidocaine).
8.3
Sample Size
The study sample size is limited to 10 subjects receiving the Basmati Injectrode insert.
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9.0 Methods and Procedure
9.1
DATA COLLECTION REQUIREMENTS
Subject data will be collected and documented on case report forms (CRFs). Templates of the CRFs for
this study are located in Appendix 17.
9.1.1
Subject Screening Procedure
Subjects will be chosen from healthy volunteer candidates. Potential study participants must pass a
thorough general medical exam. Subjects may either be male or female and must meet all the study's
eligibility criteria which are typical eligibility criteria for early feasibility studies. They will be
required to sign an informed consent form prior to being asked to participate in the study, undergoing
any study-related procedures or having any data collection occurring.
Assessments and Data Collection
Screening
and
Enrollment
Call for
patch
removal
Injectrode
Placement
Follow-
up visits
Efficacy and
Explant visit
Post study
follow-up
Day (relative vs. Placement)
-5 to -4
-2
0
7 ± 2
14 ± 2
28 (-2 to 0)
48 ± 2
●
Eligibility confirmation
✓
●
Medical history
●
Physical exam
✓
✓
●
Informed consent
✓
●
Record demographics
●
Verification of absence of allergy
to gold & pregnancy test
●
Confirmation of study eligibility
✓
✓
✓
●
Gold skin patch test placement
✓
●
Removal of skin patch
✓
●
Read skin test patch results
✓
●
Basmati placement procedure
●
Ultrasound & Fluoroscopy image
capture
✓
✓
✓
(pre & post)
(✓)
●
Capture of images of surgical site
●
Remove skin suture(s) if placed
during surgery
✓
✓
(post)
✓
(✓)
✓
✓
(✓)
●
Measure
impedance
needle
to
needle connection
●
Measure stimulation thresholds
●
Removal procedure
●
Study participant exit
✓
✓
✓
✓
Table 2: Focus on Screening and Enrollment
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9.1.2
Informed Consent
Informed consent is defined as legally effective, documented confirmation of a subject’s (or their
legally authorized representative’s or guardian’s) voluntary agreement to participate in a particular
clinical investigation after information has been given to the subject on all aspects of the clinical
investigation relevant to the subject’s decision to participate. When a subject signs and dates the
informed consent form, he/she is considered a subject enrolled in the study.
Prior to initiation of any study-specific procedures, subjects (or their legally authorized representative
or guardian) must sign and date the informed consent form and Health Insurance Portability and
Accountability Act (HIPAA) authorization, or equivalent, where required by law and IRB.
Documentation that consent was obtained prior to any study-related procedures must be maintained in
the subject’s case history.
9.1.3
SCREENING and ENROLLMENT VISIT (IN-PERSON, day -5 or day -4)
Once the informed consent has been documented, the study participant's eligibility for study
participation is verified at the Enrollment Visit. During this assessment, the study physician will collect
and
document
each
potential
participant’s
relevant
medical
history
(including
diagnosis),
demographics and physical examination results. The visit concludes with the placement of the allergy
skin test patch on the arm of the study participant. The gold allergy skin test patch is essentially a small
band-aid filled with gold salt. According to the test’s instruction for use, the patch must be placed on
the skin for two to three days prior to an additional waiting period of two more days before the skin
reaction can be interpreted by the physician. Accordingly, the next two visits are scheduled with the
study participant as (1) a phone call to remove the skin test while creating a record in the
corresponding CRF (see 9.1.4 below) and the (2) actual in-person Insert Placement Visit with a
two-day delay following the phone call.
9.1.4
ALLERGY TEST PATCH REMOVAL VISIT (CALL, day -2)
The first follow-up visit is a phone call scheduled for two (three) days after the Enrollment Visit. The
study participant is asked to remove the gold allergy skin test patch and a record of the removal is
made in the corresponding CRF for that visit. The scheduling of the Insert Placement Visit for two
days later is verified with the study participant.
9.1.5
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9.1.6
INSERT PLACEMENT VISIT (IN-PERSON, day 0)
The Insert Placement Visit begins with an examination of the study participant’s arm to capture and
interpret the result of the gold allergy skin test by the physician. Once the absence of a gold allergy is
verified, the participant advances to the group of up to 10 participants that will receive the Basmati
Injectrode insert.
Appropriately trained field staff will assist as necessary with the Basmati Injectrode insert procedure.
The recommended placement location for the device on the left or the right hip region (figure 6) will
be determined by the physician and documented on the CRF.
Figure 6: Depiction of the surgical location (arrows). Placement of the Basmati Injectrode is the hip region of the
study participant at approximately the height of the naval.
Prior to the placement of the insert, the surgical location near the hip, approximately at the height of
the naval, is cleaned and sterilized following standard OR procedures (betadine, 70% isopropyl
alcohol). Following an injection of subcutaneous lidocaine (1%), a small (~5mm) incision is made
using a scalpel followed by blunt dissection of the subcutaneous tissue. Blunt dissection technique is
used to create a tunnel of about 3-5 mm diameter, at a depth of approximately 2mm measured from the
surface of the skin, and up to 2 cm long (figure 7, A).
Figure 7: Approximate dimensions of the tunnel placed at the hip region prior to (A) and following (B) the placement
of the Basmati Injectrode insert.
Using the deployment device, the Basmati Injectrode is placed into the distal end of the tunnel, leaving
a length of approximately 1 cm of empty tunnel between the Basmati and the skin incision (Figure 7,
B). At the clinician's discretion, pressure to the wound channel alone or surgical glue may be used to
ensure proper adherence of the tunnel walls to close the length of the tunnel. The skin incision may be
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closed with steri-strips, surgical glue or one or more small suture loops as per the physician’s
discretion.
Pain management will be provided post surgery based on physician discretion.
Information regarding the devices used, location and procedure data will be collected on an Insert
placement section of the CRF. With the study participant's and the surgeon's consent, Neuronoff’s
representative may be present during the insert procedure.
The steps taken during the Injectrode Placement Procedure vist are further outline in the table below:
Assessments and Data Collection
Screening
and
Enrollment
Call for
patch
removal
Injectrode
Placement
Follow-
up visits
Efficacy and
Explant visit
Post study
follow-up
Day (relative vs. Placement)
-5 to -4
-2
0
7 ± 2
14 ± 2
28 (-2 to 0)
48 ± 2
●
Eligibility confirmation
✓
●
Medical history
●
Physical exam
✓
✓
●
Informed consent
✓
●
Record demographics
●
Verification of absence of allergy
to gold & pregnancy test
●
Confirmation of study eligibility
✓
✓
✓
●
Gold skin patch test placement
✓
●
Removal of skin patch
✓
●
Read skin test patch results
✓
●
Basmati placement procedure
●
Ultrasound & Fluoroscopy image
capture
✓
✓
✓
(pre & post)
(✓)
●
Capture of images of surgical site
●
Remove skin suture(s) if placed
during surgery
✓
✓
(post)
✓
(✓)
✓
✓
(✓)
●
Measure
impedance
needle
to
needle connection
●
Measure stimulation thresholds
●
Removal procedure
●
Study participant exit
✓
✓
✓
✓
Table 3: Focus on the Injectrode Placement visit
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9.1.7
FOLLOW-UP VISITS (IN-PERSON or CALL, day 7 and day 14)
Follow-up visits will occur on day 7 (+/–2) and 14 (+/–2) post-procedure. Data collected at these visits
will be recorded on case forms (CRFs) and will include the bolded (grayed) portion:
Assessments and Data Collection
Screening
and
Enrollment
Call for
patch
removal
Injectrode
Placement
Follow-
up
visits
Efficacy and
Explant visit
Post study
follow-up
Day (relative vs. Placement)
-5 to -4
-2
0
7 ± 2
14 ± 2
28 (-2 to 0)
42 ± 2
●
Eligibility confirmation
✓
●
Medical history
●
Physical exam
✓
✓
●
Informed consent
✓
●
Record demographics
●
Verification of absence of allergy
to gold & pregnancy test
●
Confirmation of study eligibility
✓
✓
✓
●
Gold skin patch test placement
●
Removal of skin patch
✓
●
Read skin test patch results
✓
●
Basmati placement procedure
●
Ultrasound & Fluoroscopy image
capture
✓
✓
✓
(pre & post)
(✓)
●
Capture of images of surgical site
●
Remove skin suture(s) if placed
during surgery
✓
✓
(post)
✓
(✓)
✓
✓
(✓)
●
Measure
impedance
needle
to
needle connection
●
Measure stimulation thresholds
●
Removal procedure
●
Study participant exit
✓
✓
✓
✓
Table 4: Focus on follow-up visits
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9.1.8
EFFICACY & EXPLANT VISIT (IN-PERSON, day 28)
This visit has two parts. The total duration of this visit is expected to be approximately 1 hour.
The first part of the visit is focused on capturing stimulation thresholds of cutaneous afferent nerves to
provide information about the Injectode’s capabilities to conduct current at low electrical impedance
values. This first part is anticipated to last for approximately 30 minutes and scheduled to occur just
before the explant of the Basmati Injectrode insert.
The second part of the visit is the actual explant of the device that will then be sent to histopathology
for further processing. This second part is anticipated to last for approximately 30 minutes and will
include image capturing for purposes of documentation.
Part I: Impedance and stimulation threshold data acquisition
Materials:
Stimulation will be provided using a DS7A Constant Current Stimulator unit (Digitimer), a device
with CE and FDA clearance. Electrical impedance will be measured with a handheld, battery-powered
oscilloscope (Fluke ScopeMeter) that is certified and calibrated. Sterile clinical grade standard needles
intended for single patient use (30 gauge) will be used to directly interface percutaneously with the
Injectrode. Details for this interfacing approach are provided below. A clinical grade, disposable,
surface patch electrode will be used as a distal return, referred to as a TENS electrode/patch in this
document. The Stimulator, Oscilloscope, Needles and TENS electrodes will be connected together
using standard leads (Pamona, Comed).
Methods:
The setup for these stimulation and impedance tests are done under two types of visualization. First,
visualization is done via ultrasound according to a Mohs’ surgery plan. Second, the setup is visualized
with fluoroscopy to ensure that the needles are placed precisely within the subcutaneously implanted
Basmati Injectrode.
All equipment will be turned on prior to use, followed by connecting the Stimulator in parallel to the
Oscilloscope as shown in Figures 7a through 7e below. Data will be recorded for every measurement.
Prior to beginning the measurements, test leads will also be hooked up to the stimulator in parallel.
Generally, measurements during this visit will be recorded at a current amplitude ranging between 0.1
and 10 mA and pulse widths ranging from 50 µsec to 1500 µsec. Reference impedance values will be
recorded at a current amplitude at 1mA and a pulse width of 200 µsec using a reference resistor of 1
kOhm. The sensory stimulation thresholds (“Measurement 1” through “Measurement 3.3”) below will
be conducted with a preferred pulse width of 100 µsec and 200 µsec, and, if need be, may be measured
once more with a different pulse width in the range between 50 µsec to 1500 µsec to be able to capture
stable measurements.
In order to record sensory afferent nerve responses to electrical stimulation, it is imperative that
lidocaine is not injected at the site of the Injectrode for the entity of part 1. Instead, the skin above the
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Injectrode is cleaned using 70% Isopropyl alcohol at the site of the Injectrode with a margin of 3cm
around the site, identified via palpation of the skin. Two 30 gauge needles are inserted through the
cleaned skin into the Injectrode as shown in Figures 8a through 8e. At a location 1-2cm away from the
Injectrode, a third 30 gauge needle will be inserted as shown in Figure 8a. Finally, at a location
approximately 10 cm away from the Injectrode, a TENS patch electrode will be placed to function as
the return electrode for electrical current. Test leads with hooked ends will be attached to the needle
shaft extending out of the skin and taped to the skin to keep the leads secure and from pulling on the
needles should the study participant or lead move.
Measurement 1: Once the leads are properly attached to the needles and TENS patch, testing may
commence. The first measurement will establish the stimulation activation (sensation) threshold of
afferent nerves in the skin of the hip region of the study participant in the vicinity of where the
Injectrode is present. Needle D and TENS patch C will first be connected to the stimulator (as shown
in figure 8a), and step wise increments in stimulus amplitude will be performed until the study
participant notes that they can perceive the stimulation (e.g. step size amplitude = 100 µA, pulse width
= 200 µsec). The study participant will be asked to report when they perceive a paresthesia, essentially
a tingling sensation of the skin. The current and pulse width values for the initial report of paresthesia
will be recorded and may be verified with a second measurement. The values allowing the study
participant to perceive a tingling paresthesia sensation are expected to be an order of magnitude
smaller than currents needed to cause the perception of pain. If the study participant reports pain
during the stimulation then the clinician will adjust their testing approach accordingly to avoid such
participant feedback. Once the stimulation activation threshold is determined, lead D may be
unplugged and needle D removed from the skin.
Figure 8a: Stimulus activation setup of electrodes for measurement #1.
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A series of three stimulation tests will be performed between the Injectrode (A, B) and the TENS patch
(C), as shown in Figures 8c, 8d, and 8e. The first stimulation for each measurement will be performed
at or below the stimulation threshold established in measurement 1 for the study participant. The study
participant will be asked whether they sensed the stimulus, and their answer recorded. If needed, the
stimulation current will be increased in increments of 100 µA of current or 50-100 µsec of pulse
duration until the study participant perceives the stimulus.
In measurement 2 (Figure 8b), needle A and the TENS surface patch electrode (C) will be hooked up
to the stimulator and oscilloscope.
Figure 8b: Impedance and Stimulation setup of electrodes for measurement #2.
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In measurement 3 (Figure 8c), needle B and the TENS surface patch electrode (C) will be hooked up
to the stimulator and oscilloscope.
Figure 8c: Stimulation setup of electrodes for measurement #3.
In measurement 4 (Figure 8d), needles A and B will be connected together to one output/input, while
the TENS surface patch electrode (C) will be hooked up to the other output/input of the stimulator and
oscilloscope.
Figure 8d: Stimulation setup of electrodes for measurement #4.
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Measurement 5: Lastly, needles A and B will be hooked up to the stimulator as shown in Figure 8e.
Electrical stimulation at the stimulus activation threshold will be applied. The study participant will be
asked if they still perceive the stimulation at threshold. If they do not, another stimulus activation
threshold test will be performed (e.g. step size amplitude = 100 µA, pulse width = 200 µsec) up to 10
mA of current. After each stimulation, the study participant will be asked if they perceived the
stimulation, with perception noted as the stimulus activation threshold of current passing through the
injectrode. It is expected that the threshold in Measurement 5 will be at least five times higher than that
recorded in Measurement 1, as a result of the conductive injectrode shunting (short-circuiting) current
between the two needles, thus making it harder to stimulate nerves near the Injectrode. Recorded data
from the oscilloscope will be used to calculate the impedance of the Basmati Injectrode.
Figure 8e: Stimulation setup of electrodes for measurement #5.
The resulting table of amplitudes and pulse widths resulting from each measurement will be recorded
in the CRF.
This closes part 1 of the efficacy and explant visit. The skin at the location of the Injectrode will now
be cleaned once more and prepared for surgical removal of the Basmati Injectrode insert.
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Part II: Explant (Device Removal)
Methods:
The explant surgical plan will be verified with images from ultrasound and fluoroscopy taken earlier
the same day. The explant is a Mohs style surgery. The injection site is anesthetized via lidocaine
(solution 1%), and a sharp cut is made above the Basmati Injectrode. Next, tissue forceps are used to
hold onto the device while dissection is performed around the Injectrode in naïve tissue at a target
distance of about 0.5 to 1 mm.
Once removed, the explanted Basmati Insert is placed in a glass vial containing Formalin (10%
formaldehyde solution), labeled in code with sequential numbers for each study participant in
compliance with HIPAA requirements. The subsequent wound is closed, in layers if applicable. The
incision is closed with steri-strip, surgical skin glue or sutures as per the surgeon’s discretion. The
closed wound is then bandaged as per standard protocol.
At no time from explant to histological analysis report generation will Neuronoff, Inc. be in possession
of the device, samples, or data. The device will be left in Formalin for 24 hours, at which time the
solution will be exchanged for 70% ethanol by the clinical site. The fixed samples will then be shipped
to the following location, with email notifications to Jennifer Mikulan (CWRU Tissue Resource Core,
jjm10@case.edu) containing the subject “BASMATI Sample Submission” along with shipping
tracking information and subject de-identified sample number:
CWRU Tissue Resource Core
Attn: Jennifer Mikulan
2058 University Hospitals Drive
Wearn Bldg. Rm #333
Cleveland, Ohio 44106
Histological slides generated by the Tissue Resource Core will then be transferred to an independent
third party pathologist (Nicholas P. Ziats, Case Western Reserve University) for analysis and report
generation. Once completed, the report and samples will be sent to Neuronoff, Inc. for safekeeping.
Upon completion of the explant, the site once occupied by the Injectrode is again visualized with
ultrasound, and then again with fluoroscopy. Both visualizations will be documented.
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Summary:
Assessments and Data Collection
Screening
and
Enrollment
Call for
patch
removal
Injectrode
Placement
Follow-
up visits
Efficacy
and
Explant
visit
Post study
follow-up
Day (relative vs. Placement)
-5 to -4
-2
0
7 ± 2
14 ± 2
28 (-2 to 0)
42 ± 2
●
Eligibility confirmation
✓
●
Medical history
●
Physical exam
✓
✓
●
Informed consent
✓
●
Record demographics
●
Verification of absence of allergy
to gold & pregnancy test
●
Confirmation of study eligibility
✓
✓
✓
●
Removal of skin patch
✓
●
Read skin test patch results
✓
●
Basmati placement procedure
●
Ultrasound
&
Fluoroscopy
image capture
✓
✓
✓
(pre & post)
(✓)
●
Capture of images of surgical
site
●
Remove skin suture(s) if placed
during surgery
✓
✓
(post)
✓
(✓)
✓
✓
(✓)
●
Measure impedance needle to
needle connection
●
Measure stimulation thresholds
●
Removal procedure
●
Study participant exit
✓
✓
✓
✓
Table 5: Focus on Explant visit
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9.1.9
POST-EXPLANT VISIT & STUDY EXIT (IN-PERSON, day 42 +/- 2)
A Study Exit CRF must be completed for any subject who signed an informed consent form, as they
are considered enrolled in the study. Data to be collected at this visit include study exit date and reason
for study exit, device or procedure related AEs, technical observations/device deficiencies and surgical
interventions.
Some scenarios may lead to study exit and require completion of a Study Exit CRF: These include
subject ineligibility for the implant in the opinion of the study physician, failure to meet inclusion
criteria, meeting exclusion criteria, removal of the SCS lead without re-implantation, attempted
implant without SCS implantation, voluntary withdrawal by the subject, subject withdrawal by the
investigator, failure to maintain adequate study compliance and/or subject death.
Assessments and Data Collection
Screening
and
Enrollment
Call for
patch
removal
Injectrode
Placement
Follow-
up visits
Efficacy and
Explant visit
Post
study
follow-up
Day (relative vs. Placement)
-5 to -4
-2
0
7 ± 2
14 ± 2
28 (-2 to 0)
42 ± 2
●
Eligibility confirmation
✓
●
Medical history
●
Physical exam
✓
✓
●
Informed consent
✓
●
Record demographics
●
Verification of absence of allergy
to gold & pregnancy test
●
Confirmation of study eligibility
✓
✓
✓
●
Removal of skin patch
✓
●
Read skin test patch results
✓
●
Basmati placement procedure
●
Ultrasound
&
Fluoroscopy
image capture
✓
✓
✓
(pre & post)
(✓)
●
Capture of images of surgical
site
●
Remove skin suture(s) if placed
during surgery
✓
✓
(post)
✓
(✓)
✓
✓
(✓)
●
Measure
impedance
needle
to
needle connection
●
Measure stimulation thresholds
●
Removal procedure
●
Study participant exit
✓
✓
✓
✓
Table 6: Focus on Post study follow-up
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10.0 ADVERSE EVENT REPORTING
During the study, the investigator will determine whether any adverse events (AE’s) have occurred.
For the purpose of this protocol, an adverse event is any undesirable clinical occurrence in a subject
that can be attributed to the device or incision closure procedure.
10.1
ADVERSE EVENTS
In this study, study participants should be encouraged to report AE’s spontaneously or in response to
general, non-directed questioning (e.g., “How has your health been since the last visit?”) per
Neuronoff SOP-38. Any time during the study, the study participant may volunteer information about
any event that resembles an AE. If it is determined that an AE has occurred, the investigator should
obtain all the information required to complete the AE Form of the CRF.
The following categories of adverse event severity are to be used:
Mild
Awareness of a sign or symptom that does not interfere with the
study participant's usual activity or is transient, resolved without
treatment and with no sequelae
Moderate
Interferes with the study participant's usual activity
Severe
Any fatal or immediately life-threatening clinical experience that
requires a subject to be hospitalized, or hospitalization is unduly
prolonged because of potential disability or danger to life or
because an intervention has been necessitated.
This includes
events
that
cause
fetal
distress,
fetal
death,
congenital
abnormality or malignancy or any permanently disabling event.
Table 7: Categories of adverse event severity
10.2
ANTICIPATED ADVERSE DEVICE EFFECTS
The following ANTICIPATED EVENTS have been identified as possible complications of
participation in the study.
•
Infection at implant site
•
Pain at implant site
•
Bleeding
•
Bruising
•
Itch
•
Allergic reaction
To minimize the risk of any study participant developing an allergic reaction to the Basmati insert’s
sole material (gold of 99.99% purity), a gold skin test will be performed during the first study visit.
Patients only advance to the implant visit after a negative skin allergy test to gold has been confirmed.
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10.3
UNANTICIPATED ADVERSE DEVICE EFFECTS
Unanticipated adverse device effects 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 investigational plan
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.
For the purposes of this study, serious is defined as any significant adverse experience, including those
which may be either life-threatening or involve permanent or long term injuries, but excluding injuries
that are non-life-threatening and that are temporary and reasonably reversible.
An Investigator must submit to the sponsor and to the responsible Medical Ethics Committee (
IRB ) any unanticipated adverse device effects that occur during the study as soon as possible,
but in no circumstances later than ten (10) working days after the Investigator first learns of the
effect.
Mild
Submit to IRB per local reporting requirements.
Moderate
Submit as soon as possible but no later than 10 working days after the
Investigator first learns of the event.
Severe
Submit as soon as possible but no later than 10 working days after the
Investigator first learns of the event, or per local reporting requirements,
whichever is more conservative.
Table 8: Categories of adverse event severity and triggered processes
Contact Name:
Amol Soin, MD
Ohio Pain Clinic
7076 Corporate Way
Dayton, OH 45458
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The study investigator adverse event reports are listed in Table 9 below:
Report
Submit To
Description/Contraints
Death
Sponsor
Submit as soon as possible but no later than 10
working days after the Investigator first learns of
the event.
IRB
Submit to IRB per local reporting requirements
Unanticipated
adverse device
effect (UADE)
Sponsor
Submit as soon as possible but no later than 10
working days after the Investigator first learns of
the event.
IRB
Submit as soon as possible but no later than 10
working days after the Investigator first learns of
the event
Other Adverse
Device Effects
Sponsor
Submit or report as required per local reporting
requirements.
IRB
Submit or report as required per local IRB
reporting requirements.
Regulatory Body
Submit or report as required per regulations.
Table 9: Investigator adverse event reports
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11.0 STATISTICS
11.1
Study Population
All study participants who received treatment will be included in a statistical analysis. Any protocol
deviations will also be reported.
11.2
Observational Pilot Study
As this is a first in human pilot study, this study will not be powered for statistical analysis. Instead, a
representative number of 10 participants will be selected.
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12.0 ETHICS
12.1
Medical Ethics Committee ( IRB ) Review
Prior to initiation of the study, the Principal Investigator (PI) will submit the study protocol, sample
Informed Consent Form and any other documents that may be requested by the IRB for review and
approval. The PI will request that the IRB provide written approval of the study and keep on file all
IRB correspondence, including records of approval of all documents pertaining to this study. If the
IRB imposes any additional requirements (e.g. safety reports, progress reports etc.), the Sponsor will
prepare the required documents and send them to the Investigator for reporting to the IRB.
12.2
Ethical Conduct of the Study
This study will be conducted in compliance with the protocol, good clinical practices (GCP), and the
applicable regulatory requirements.
12.3
Study participant Information and Consent
Prior to screening for the study, each study participant, as required, will be informed in detail about the
nature of the clinical investigation with its expected risks and discomforts. The basic elements of
informed consent as specified by the EU Directive 2001/20/EC will be followed. Written consent will
be obtained from each study participant enrolled in the clinical study, as required, using the IRB
-approved Informed Consent Form (ICF). The PI will verify the consent form. Each study participant
will be given a copy of the Informed Consent Form. The study participants will also be instructed that
they are free to withdraw their consent and discontinue their participation in the study at any time
without prejudice.
Prior to the start of the study, the PI will be provided with an actual stamped
Informed Consent Form approved by the IRB for use during the study. At the conclusion of the
study, the PI will provide a letter stating that a signed informed consent was obtained from each of the
study participants. The signed informed consent forms will be kept on file in a secured, designated
place at the study site for the required period of time.
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13.0 STUDY ADMINISTRATION
13.1
Study Initiation
Prior to the start of this study, all pre-investigational requirements must be met by the PI and study site.
Compliance will be confirmed by the study monitor during the pre-study visit. The pre-investigational
requirements may include:
1. Current Curriculum Vitae and current medical licenses or medical numbers of the PI and all
sub-investigators
2. IRB
name and address; Department of Health and Human Services (DHHS) number, if
applicable, or membership list
3. Written documentation of IRB approval of protocol (identified by protocol number and title)
and informed consent document (identified by protocol number and title)
4. A copy of the IRB approved consent form
5. A signed Clinical Research Agreement.
13.2
Clinical Supplies
The PI will be responsible for the dispensing, inventory and accountability of all clinical supplies,
exercising accepted medical practices. An accurate and timely record of the disposition of all clinical
supplies must be maintained. The supplies and inventory record must be made available for inspection
by the Clinical Monitor upon request. Upon completion or termination of the study the PI will return
all remaining clinical supplies to Neuronoff, Inc., or designee along with a copy of the inventory
record and a record of the clinical supplies returned. Under no circumstances will the PI allow the
investigational device to be used other than as directed by this protocol.
13.3
Case Report Forms (CRFs)
Neuronoff, Inc. will provide the CRFs. The PI will be responsible for the timeliness, completeness
and accuracy of the information on the CRF. All entries must be legibly recorded in ink, with entry
errors designated by a single-line cross out, initiated and dated, such that the original entry remains
readable. If electronic records are used,
The PI will make these forms available for review and collection by the designated representative at
each scheduled monitoring visit.
The PI will retain a file copy of each completed CRF. In addition, the PI will ensure that the monitor
representative(s) have access to source documents (e.g., hospital and clinic records) to ensure accuracy
and completeness of the CRFs during the periodic reviews.
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13.4
Study Completion
Data and materials that are required before the study can be considered complete and/or terminated
are:
•
Laboratory findings, clinical data and all special test results from treatment through the
end of the follow-up period
•
CRFs (including correction forms) properly completed by appropriate study personnel and
signed by the PI
•
Completed Device Accountability Records
•
Statement of outcome for each unanticipated adverse device effect reported
•
Copies of protocol amendments and IRB approvals (if applicable)
13.5
Final Report
The purpose of this single center pilot study is to assess the safety and interface efficacy performance
of the Neuronoff Basmati Insert. The results will be presented in a clinical report with the study data
provided by the Primary Investigator (PI).
13.6
Retention of Study Records
The PI will retain copies of the approved protocol, completed CRFs, informed consent documents,
relevant source documents, study-related correspondence and all other supporting documentation
related to the project for the latter of a period of 2 years following the approval of a premarket
application (U.S.) or 2 years from the time the study is terminated.
These files must be made available for inspection upon reasonable request by authorized
representatives of the Ohio Pain Clinic.
13.7
Confidentiality
Study participant medical information obtained by the study is confidential, and disclosure to third
parties other than those noted below is prohibited. We will follow HIPAA guidelines toward study
participant information.
At the study participant's request, medical information may be given to his or her personal physician or
other appropriate medical personnel responsible for his or her welfare.
Data generated by this study must be available for inspection on request by representatives of
Neuronoff, and the IRBs (if appropriate).
The information obtained in this study may be published in medical journals, but will not reveal the
identity of the individual study participants.
13.8
Publication of Study Results
Results of this study will not be submitted for presentation or publication without the prior written
permission of Neuronoff, Inc.
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14.0 SIGNATURE of PRINCIPAL INVESTIGATOR
I have read the study protocol, entitled BASMATI - Basic Assessment of Safety and Minimally
invAsive sTimulation via Injectrode.
I agree to conduct the investigation in accordance with the
agreement, the investigational plan and applicable EU and US regulations. Further, I agree to conduct
the investigation in accordance with the conditions imposed by the reviewing IRB. This includes the
supervision of the device involving human study participants and ensuring that the requirements for
obtaining informed consent are met.
Printed name of Principal Investigator
Date
Signature of Principal Investigator
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15.0 Declaration of Helsinki
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
 Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000
1.
INTRODUCTION
1.
The World Medical Association has developed the Declaration of Helsinki as a statement of
ethical principles to provide guidance to physicians and other participants in medical
research involving human subjects. Medical research involving human subjects includes
research on identifiable human material or identifiable data.
2.
It is the duty of the physician to promote and safeguard the health of the people. The
physician's knowledge and conscience are dedicated to the fulfillment of this duty.
3.
The Declaration of Geneva of the World Medical Association binds the physician with the
words, "The health of my study participant will be my first consideration," and the
International Code of Medical Ethics declares that, "A physician shall act only in the study
participant's interest when providing medical care which might have the effect of weakening
the physical and mental condition of the study participant."
4.
Medical progress is based on research which ultimately must rest in part on experimentation
involving human subjects.
5.
In medical research on human subjects, considerations related to the well-being of the human
subject should take precedence over the interests of science and society.
6.
The primary purpose of medical research involving human subjects is to improve
prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology
and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic
methods must continuously be challenged through research for their effectiveness, efficiency,
accessibility and quality.
7.
In current medical practice and in medical research, most prophylactic, diagnostic and
therapeutic procedures involve risks and burdens.
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8.
Medical research is subject to ethical standards that promote respect for all human beings
and protect their health and rights. Some research populations are vulnerable and need
special protection. The particular needs of the economically and medically disadvantaged
must be recognized. Special attention is also required for those who cannot give or refuse
consent for themselves, for those who may be subject to giving consent under duress, for
those who will not benefit personally from the research and for those for whom the research
is combined with care.
9.
Research Investigators should be aware of the ethical, legal and regulatory requirements for
research on human subjects in their own countries as well as applicable international
requirements. No national ethical, legal or regulatory requirement should be allowed to
reduce or eliminate any of the protections for human subjects set forth in this Declaration.
2.
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
1.
It is the duty of the physician in medical research to protect the life, health, privacy, and
dignity of the human subject.
2.
Medical research involving human subjects must conform to generally accepted scientific
principles, be based on a thorough knowledge of the scientific literature, other relevant
sources of information, and on adequate laboratory and, where appropriate, animal
experimentation.
3.
Appropriate caution must be exercised in the conduct of research which may affect the
environment, and the welfare of animals used for research must be respected.
4.
The design and performance of each experimental procedure involving human subjects
should be clearly formulated in an experimental protocol. This protocol should be submitted
for consideration, comment, guidance, and where appropriate, approval to a specially
appointed ethical review committee, which must be independent of the investigator, the
sponsor or any other kind of undue influence. This independent committee should be in
conformity with the laws and regulations of the country in which the research experiment is
performed. The committee has the right to monitor ongoing trials. The researcher has the
obligation to provide monitoring information to the committee, especially any serious
adverse events. The researcher should also submit to the committee, for review, information
regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and
incentives for subjects.
5.
The research protocol should always contain a statement of the ethical considerations
involved and should indicate that there is compliance with the principles enunciated in this
Declaration.
6.
Medical research involving human subjects should be conducted only by scientifically
qualified persons and under the supervision of a clinically competent medical person. The
responsibility for the human subject must always rest with a medically qualified person and
never rest on the subject of the research, even though the subject has given consent.
7.
Every medical research project involving human subjects should be preceded by careful
assessment of predictable risks and burdens in comparison with foreseeable benefits to the
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subject or to others. This does not preclude the participation of healthy volunteers in medical
research. The design of all studies should be publicly available.
8.
Physicians should abstain from engaging in research projects involving human subjects
unless they are confident that the risks involved have been adequately assessed and can be
satisfactorily managed. Physicians should cease any investigation if the risks are found to
outweigh the potential benefits or if there is conclusive proof of positive and beneficial
results.
9.
Medical research involving human subjects should only be conducted if the importance of
the objective outweighs the inherent risks and burdens to the subject. This is especially
important when the human subjects are healthy volunteers.
10. Medical research is only justified if there is a reasonable likelihood that the populations in
which the research is carried out stand to benefit from the results of the research.
11. The subjects must be volunteers and informed participants in the research project.
12. The right of research subjects to safeguard their integrity must always be respected. Every
precaution should be taken to respect the privacy of the subject, the confidentiality of the
study participant's information and to minimize the impact of the study on the subject's
physical and mental integrity and on the personality of the subject.
13. In any research on human beings, each potential subject must be adequately informed of the
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations
of the researcher, the anticipated benefits and potential risks of the study and the discomfort
it may entail. The subject should be informed of the right to abstain from participation in the
study or to withdraw consent to participate at any time without reprisal. After ensuring that
the subject has understood the information, the physician should then obtain the subject's
freely-given informed consent, preferably in writing. If the consent cannot be obtained in
writing, the non-written consent must be formally documented and witnessed.
14. When obtaining informed consent for the research project the physician should be
particularly cautious if the subject is in a dependent relationship with the physician or may
consent under duress. In that case the informed consent should be obtained by a
well-informed physician who is not engaged in the investigation and who is completely
independent of this relationship.
15. For a research subject who is legally incompetent, physically or mentally incapable of giving
consent or is a legally incompetent minor, the investigator must obtain informed consent
from the legally authorized representative in accordance with applicable law. These groups
should not be included in research unless the research is necessary to promote the health of
the population represented and this research cannot instead be performed on legally
competent persons.
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent to
decisions about participation in research, the investigator must obtain that assent in addition
to the consent of the legally authorized representative.
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17. Research on individuals from whom it is not possible to obtain consent, including proxy or
advance consent, should be done only if the physical/mental condition that prevents
obtaining informed consent is a necessary characteristic of the research population. The
specific reasons for involving research subjects with a condition that renders them unable to
give informed consent should be stated in the experimental protocol for consideration and
approval of the review committee. The protocol should state that consent to remain in the
research should be obtained as soon as possible from the individual or a legally authorized
surrogate.
18. Both authors and publishers have ethical obligations. In publication of the results of research,
the investigators are obliged to preserve the accuracy of the results. Negative as well as
positive results should be published or otherwise publicly available. Sources of funding,
institutional affiliations and any possible conflicts of interest should be declared in the
publication. Reports of experimentation not in accordance with the principles laid down in
this Declaration should not be accepted for publication.
3.
ADDITIONAL
PRINCIPLES
FOR
MEDICAL
RESEARCH
COMBINED
WITH
MEDICAL CARE
1.
The physician may combine medical research with medical care, only to the extent that the
research is justified by its potential prophylactic, diagnostic or therapeutic value. When
medical research is combined with medical care, additional standards apply to protect the
study participants who are research subjects.
2.
The benefits, risks, burdens and effectiveness of a new method should be tested against those
of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude
the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or
therapeutic method exists.
3.
At the conclusion of the study, every study participant entered into the study should be
assured of access to the best proven prophylactic, diagnostic and therapeutic methods
identified by the study.
4.
The physician should fully inform the study participant which aspects of the care are related
to the research. The refusal of a study participant to participate in a study must never
interfere with the study participant-physician relationship.
5.
In the treatment of a study participant, where proven prophylactic, diagnostic and therapeutic
methods do not exist or have been ineffective, the physician, with informed consent from the
study participant, must be free to use unproven or new prophylactic, diagnostic and
therapeutic measures, if in the physician's judgment it offers hope of saving life,
re-establishing health or alleviating suffering. Where possible, these measures should be
made the object of research, designed to evaluate their safety and efficacy. In all cases, new
information should be recorded and, where appropriate, published. The other relevant
guidelines of this Declaration should be followed.
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16.0 REFERENCES, REGULATIONS AND STANDARDS
16.1
References
1.
American Chronic Pain Association Resource Guide to Chronic Pain Medication and
Treatment, 2014 Edition.
2.
Trevathan JK, Baumgart I, Nicolai EN, et al. A Truly Injectable Neural Stimulation
Electrode Made From an In-Body Curing Polymer/Metal Composite. BioRxiv. 2019
BioRxiv https://doi.org/10.1101/584995.
3.
Deer TR, Levy RM, Rosenfeld EL. Prospective Clinical Study of a New Implantable
Peripheral Nerve Stimulation Device to Treat Chronic Pain. Clin J Pain. 2010
Jun;26(5):359-72. https://doi.org/10.1097/AJP.0b013e3181d4d646
4.
Deer TR, Pope JE, Kaplan M. A novel method of neurostimulation of the peripheral
nervous system: The StimRouter implantable device. Tech Reg Anes Pain Manag. 2012
Apr;16(2):113-117. https://doi.org/10.1053/j.trap.2013.02.007
5.
Deer T, Pope J, Benyamin R, Vallejo R, Friedman A, Caraway D, Staats P, Grigsby E,
McRoberts WP, McJunkin T, Shubin R, Vahedifar P, Tavanaiepour D, Levy R, Kapural L,
Medhail N. Prospective, Multicenter, Randomized, Double-Blinded, Partial Crossover
Study to Assess the Safety and Efficacy of the Novel Neuromodulation System in the
Treatment of Patients With Chronic Pain of Peripheral Nerve Origin. Neuromodulation.
2016 Jan;19(1):91-100: https://doi.org/10.1111/ner.12381
6.
Acute Human Study: StimRouter for Peripheral Nerve Stimulation of Discrete Peripheral
Nerves (SimRouter). First Posted April 23, 2008.
https://clinicaltrials.gov/ct2/show/NCT00665132?id=NCT00665132+OR+NCT01592344
&draw=2&rank=2&load=cart
7.
Bioness® StimRouter™Neuromodulation System for Chronic Pain Therapy. First Posted
May 7, 2012.
https://clinicaltrials.gov/ct2/show/NCT01592344?id=NCT00665132+OR+NCT01592344
&draw=2&rank=1&load=cart
8.
Geddes, L.A., Roeder, R. Criteria for the Selection of Materials for Implanted Electrodes.
Annals of Biomedical Engineering 31, 879–890 (2003).
https://doi.org/10.1114/1.1581292
9.
Hielm-Bjorkman A, Raekallio M, Kuusela E, Saarto E, Markkola A, Tulamo RM.
Double-blind evaluation of implants of gold wire at acupuncture points in the dog as a
treatment for osteoarthritis induced by hip dysplasia. Vet Rec. 2001;149(15):452-456.
https://doi.org/10.1136/vr.149.15.452
10. Product: Soft Tissue Marker
Composed of 99.95% Gold
https://www.accessdata.fda.gov/cdrh_docs/pdf3/k031206.pdf
https://www.accessdata.fda.gov/cdrh_docs/pdf9/K091645.pdf
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11. Product: Gold Eyelid Weight Implants
Composed of 99.99% Gold
https://www.accessdata.fda.gov/cdrh_docs/pdf/K971242.pdf
https://www.accessdata.fda.gov/cdrh_docs/pdf15/K150986.pdf
16.2
FDA guidance on Good Clinical Regulations for medical
device studies
12. 21CFR820 Quality System Regulation
13. 21CFR50 Protection of Human Subjects
14. 21CFR54 Financial Disclosure by Clinical Investigators
15. 21CFR56 Institutional Review Boards
16. 21CFR812 Investigational Device Exemption
17. 21CFR814 Premarket Approval of Medical Devices
18. 21CFR822 Postmarket Surveillance
19. ICH Guideline on Good Clinical Practice
20. FDA Guidance on Investigator Responsibilities:
Protection the Rights, Safety, and
Welfare of Study Subjects.
16.3
ISO Standards
21. ISO 13485 Quality Management System
22. ISO 14971 Risk Management for medical devices
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17.0 APPENDIX 1: Figures and Tables
17.1
Figures
Figure 1: Comparison - Target Product and BASMATI Injectrode
Page 2
Figure 2: Representative histological image (Trichrome Stained)
Page 7
Figure 3: Basmati Injectrode
Page 9
Figure 4: Basmati Injectrode System Assembly in a sterilization pouch
Page 10
Figure 5: Basmati Injectrode Delivery Device
Page 11
Figure 6: Depiction of surgical location
Page 21
Figure 7: Approximate dimensions, tunnel for Basmati Injectrode insert
Page 21
Figures 8a-8e: Impedance and Stimulation setup of electrodes
Pages 25-28
17.2
Tables
Table 1: Assessments and data collection
Page 13
Table 2: Focus on Screening and Enrollment
Page 19
Table 3: Focus on the Injectrode Placement visit
Page 22
Table 4: Focus on follow-up visits
Page 23
Table 5: Focus on Explant visit
Page 30
Table 6: Focus on Post study follow-up
Page 31
Table 7: Categories of adverse event severity
Page 32
Table 8: Categories of adverse event severity and triggered processes
Page 33
Table 9 Investigator adverse event reports
Page 34
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18.0 APPENDIX 2: Included Documents & Components List
18.1
List of Included Documents
NDD-001
Injectrode Device Description
SOP-36-F1
Informed Consent Checklist
SOP-36-F2
Informed Consent Form
SOP-36-F3
Case Report Form
NCP-01-F4
Non-Significant Risk
NCP-01-WI-01
COVID-19 Mitigation Plan
REC-020
Histo-Pathology Report
SOP-02
Design Control Procedure
SOP-05
Risk Management Procedure
SOP-10
Investigator Selection Procedure
SOP-11
Clinical Site Initiation Procedure
SOP-32
Site Monitoring
SOP-33
Product Accountability
SOP-35
Site Closeout
SOP-36
Preparation of Informed Consent & Case Report Forms
SOP-34
Non-Significant Risk Studies
SOP-38
Adverse Events Reporting
18.2
List of Assembly and Component Parts
Final Assembly Part Number
Basmati Injectrode System Assembly:
F-0001
Subcomponent Part Numbers
Cannula:
C-0001
Retaining Clip:
C-0002
Basmati Injectrode:
C-0003
Plunger:
C-0004
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