Viagra Natural Da Amazonia

COMPETITIVE TECHNOLOGIES, INC.
Abbreviated Clinical Reports
In Support of
US FDA 510(k) Submission
Pain Therapy Medical Device
MC-5A
Prepared: February 2009
©2009 Competitive Technologies, Inc.
Table of Contents
Section
1.0
2.0
3.0
4.0
5.0
5.1
6.0
7.0
8.0
9.0
9.1
9.2
9.3
9.3.1
9.3.2
9.3.3
9.3.4
10.0
10.1
10.2
10.3
11.0
12.0
Page
Declaration
Introduction
Title Page
Synopsis
Table of contents of the individual clinical study
report
List of abbreviations and definition of terms
Overall study and design plan: description
Changes in conduct of the study or planned analyses
Disposition of patients
Safety evaluation
Discussion and overall conclusions
Tables, figures and graphs referred to but not included
in the text
Demographic Data Summary
Efficacy Data Summary
Safety Data Summary
Display of Adverse Events
Listings of Deaths, Other Serious and Significan
Adverse Events
Narratives of Deaths, Other Serious and Certain Other
Significant Adverse Events
Adnormal Laboratory Value Listing (each patient)
Protocol and protocol amendments
Sample Case Report Forms
Case report forms for deaths, other serious adverse
events and withdrawals for adverse events
Individual patient data listings for safety data.
Summary of efficacy evaluation
Any additional information pertinent to the evaluation
of safety
1|Page
2
3
4
8
13
13
14
15
16
20
23
26
26
27
34
34
34
34
34
35
36
42
43
45
46
DECLARATION
The clinical studies presented in this document which
were conducted using the subject medical device conform
to the ethical principles contained in the Declaration of
Helsinki, as set forth in 21CFR 814.15 (a) and (b),
incorporating the 1983 version of the Declaration, or with
the laws of Italy in which the research was conducted,
which ever provides greater protection of human
subjects.
Note to Examiner:
The device subject to this 510(k) application is the Pain Therapy Medical
Device, MC-5A. The clinical data presented herein was acquired using the
original device named Scrambler Therapy ST5. The MC-5A is identical to
the ST5 in functionality, electronics and clinical performance. The MC-5A
is the exact same as the ST5 except for minor esthetic external
modifications.
2|Page
Introduction
The purpose of this document is providing supporting valid scientific and clinical evidence of
the safety and effectiveness of the Pain Therapy Medical Device, MC-5A. The MC-5A device
uses innovative waveforms with low current intensity. The original “Scrambler Therapy
ST5” (see – Note to Examiner) received a CE mark and has been marketed in Europe since
11 November 2003 as a Class IIa (MED23015) issued by the notified body 0476. The device
is normally used in hospital services, is used for the symptomatic relief and management of
chronic intractable pain and adjunctive treatment of post-surgical or post-traumatic acute pain. It is
a prescription device and should be used under continued medical supervision. The European
Authorization is based on results of specific clinical studies performed on the device that have
been produced and accepted in support of the request for commercialization.
Minor esthetic modifications were made to the Scrambler ST5 device however it is identical in
clinical performance and functionality to the original device. The changes were described in a
Technical file and the CE Certification was issued 27 June 2008. This iteration is named
the Scrambler Therapy MC-5A device.
3|Page
Section 1.0 – Title page
Study title
Name
product
Indication
studied
ST5
Oncology
Pain
Scrambler
Therapy
ST5
Oncology
pain – high
grade not
responding
to other
treatments
ST5Abdomin
al Cancer
Scrambler
Therapy ST5
Oncology pain
– visceral
with high
grade not
responding to
other
treatments
Selfcontrolled
(1).
Unblinded.
TITLE PAGE
ST5Neuropat ST5-Randomized
hic Pain
Controlled Trial
(RCT)
Scrambler
Scrambler Therapy
Therapy ST5
ST5
ST5-Historical
Monitoring and Followup Data
Scrambler Therapy ST5
Chronic
neuropathy
pain – high
grade not
responding to
other
treatments
Selfcontrolled
(1).
Unblinded.
Prospective
study
Policlinico
Universitario
Tor Vergata Università
degli Studi di
Roma “Tor
Vergata”.
Spontaneous
Study.
Chronic neuropathy
pain – high grade not
responding to other
treatments
Chronic neuropathy pain
– high grade not
responding to other
treatments
RCT vs Multidrug
Therapy. Unblinded .
Prospective study
Self-controlled (1).
Unblinded. Prospective
study
[IRCCS] Fondazione
Ospedale Maggiore
Policlinico,
Mangiagalli, Regina
Elena, Milano.
Spontaneous Study.
Policlinico Universitario
Tor Vergata -Università
degli Studi di Roma “Tor
Vergata”. Spontaneous
Study.
ST5Abdomina
l Cancer
ST5Neuropat
hic Pain
ST5RCT01
ST5 Monitor
Design
Selfcontrolled
(1).
Unblinded.
Name of
the
sponsor
Osp.
Umberto I°
Frosinone Università
degli Studi
di Roma
“Tor
Vergata”.
Spontaneou
s Study.
ST5
Oncology
Pain
II
Osp. Umberto
I° Frosinone Università
degli Studi di
Roma “Tor
Vergata”.
Spontaneous
Study.
II
III (2)
III
IV
18/03/200
2
15/05/2002
(second
phase of
previous substudy about
visceral pain)
09/02/2004
Electronic storage files
divided by year. The
study comprises all
patients enrolled
between 01/01/1999
and 31/12/2006
NA
NA
Electronic
storage files
divided by
year. The
study
comprises all
patients
enrolled
between
01/01/2004
and
31/12/2004
NA
NA
NA
Protocol
identificati
on
Developm
ent phase
of study
Study
initiation
date (first
patient
enrolled,
or any
other
verifiable
definition)
.
Date of
early study
terminatio
n, if any.
4|Page
Study
completio
n date (last
patient
completed
).
03/06/200
2
03/06/2002
Review
(31/12/2004
)
27/08/2004
Review (31/12/2006)
Name and
affiliation
of
principal
or
coordinati
ng
investigato
r(s) or
sponsor's
responsibl
e
medical
officer.
Dott.ssa
Sandra
Spaziani.
Osp.
Umberto I°
- Frosinone.
Dott.ssa
Sandra
Spaziani. Osp.
Umberto I° Frosinone.
Prof.
Alessandro
Sabato –
Università di
Roma “Tor
Vergata”.
Dr. Vittorio Iorno –
[IRCCS] Fondazione
Ospedale Maggiore
Policlinico,
Mangiagall, Regina
Elena, Milan, Italy
Prof. Alessandro Sabato
– Università di Roma “Tor
Vergata”.
Prof.
Giuseppe
Marineo –
Delta R&D Università
di Roma
“Tor
Vergata”.
Prof.
Alessandro
Sabato –
Università
di Roma
“Tor
Vergata”.
Prof.
Giuseppe
Marineo –
Delta R&D Università di
Roma “Tor
Vergata”.
Prof.
Alessandro
Sabato –
Università di
Roma “Tor
Vergata”.
5|Page
Name of
company/s
ponsor
signatory
(the
person
responsibl
e for the
study
report
within
the
company/s
ponsor).
Responsibl
e for the
study
report:
Delta R&DUniversità
di Roma
Tor
Vergata.
Prof.
Giuseppe
Marineo.
E-mail:
g.marineo
@mclink.it
Phone:
+39065237117
3
Fax: +39-06
52371173
Other
informatio
n about
clinical
studies
execution:
Policlinico
Universitari
o “Tor
vergata”.
Department
Of Intensive
Care, Pain
Medicine
and
Anesthesiol
ogy.
Prof.
Alessandro
Sabato - Dr.
Antonello
Gatti
Direction:
+39.06.209
0.0638
Responsible
for the study
report:
Delta R&DUniversità di
Roma Tor
Vergata.
Responsible
for the study
report:
Delta R&DUniversità di
Roma Tor
Vergata.
Prof.
Giuseppe
Marineo.
E-mail:
g.marineo@m
clink.it
Prof.
Giuseppe
Marineo.
E-mail:
g.marineo@m
clink.it
Phone: +390652371173
Phone: +390652371173
Fax: +39-06
52371173
Fax: +39-06
52371173
Other
information
about
clinical
studies
execution:
Policlinico
Universitario
“Tor vergata”.
Department
Of Intensive
Care, Pain
Medicine and
Anesthesiolog
y.
Other
information
about
clinical
studies
execution:
Policlinico
Universitario
“Tor vergata”.
Department
Of Intensive
Care, Pain
Medicine and
Anesthesiolog
y.
Prof.
Alessandro
Sabato - Dr.
Antonello
Gatti
Prof.
Alessandro
Sabato - Dr.
Antonello
Gatti
Direction:
+39.06.2090.
0638
Direction:
+39.06.2090.
0638
http://www.
ptvonline.it/u
o_ter_ant_ing.
asp
http://www.
ptvonline.it/u
o_ter_ant_ing.
asp
Responsible for the
study report:
Delta R&DUniversità di Roma
Tor Vergata.
Prof. Giuseppe
Marineo.
E-mail:
[email protected]
Phone: +390652371173
Fax: +39-06
52371173
Other information
about clinical
studies execution:
IRCCS Fondazione
Ospedale Maggiore
Policlinico,
Mangiagalli, Regina
Elena. "Mario
Tiengo" Pain Centre.
Dr. Vittorio Iorno.
Phone: +39- 02
5503.2713/2714/27
11
http://ww
w.ptvonline
.it/uo_ter_a
nt_ing.asp
6|Page
Responsible for the
study report:
Delta R&D- Università di
Roma Tor Vergata.
Prof. Giuseppe Marineo.
E-mail:
[email protected]
Phone: +39-0652371173
Fax: +39-06 52371173
Other information
about clinical studies
execution:
Policlinico Universitario
“Tor vergata”.
Department Of Intensive
Care, Pain Medicine and
Anesthesiology.
Prof. Alessandro Sabato Dr. Antonello Gatti
Direction:
+39.06.2090.0638
http://www.ptvonline.it/
uo_ter_ant_ing.asp
Statement
indicating
whether
the study
was
performed
in
complianc
e with
good
clinical
practice
(GCP),
including
the
archiving
of
essential
documents
.
Date of the
report
(identify
any earlier
reports
from the
same
study by
title and
date).
The study
has been
performed
in
compliance
with
guidelines
of good
clinical
practice in
force in
Italy with
Ministry
Decree
dated 15
July 1997
and
following
updates.
The
documents
have been
stored in
the
sponsor’s
seat and
made
available
for checks
from
responsible
authorities.
29/01/200
9
The study has
been
performed in
compliance
with
guidelines of
good clinical
practice in
force in Italy
with Ministry
Decree dated
15 July 1997
and following
updates. The
documents
have been
stored in the
sponsor’s seat
and made
available for
checks from
responsible
authorities.
The study has
been
performed in
compliance
with
guidelines of
good clinical
practice in
force in Italy
with Ministry
Decree dated
15 July 1997
and following
updates. The
documents
have been
stored in the
sponsor’s seat
and made
available for
checks from
responsible
authorities.
29/01/2009
29/01/2009
The study has been
performed in
compliance with
guidelines of good
clinical practice in
force in Italy with
Ministry Decree
dated 15 July 1997
and following
updates. The
documents have
been stored in the
sponsor’s seat and
made available for
checks from
responsible
authorities.
29/01/2009
The study has been
performed in compliance
with guidelines of good
clinical practice in force
in Italy with Ministry
Decree dated 15 July
1997 and following
updates. The documents
have been stored in the
sponsor’s seat and made
available for checks from
responsible authorities.
29/01/2009
Notes:
1) The severity grade of pain in enrolled patients did not ethically allow the treatment with a
placebo. All enrolled patients did not show a meaningful response to protocol therapies,
thereby justifying a self-controlled study. The comparison with the best protocol therapies
available upon performing the study and with reference scientific literature is deemed
implicit.
2) A phase III study must be directly compared with the best protocol treatments used at that
time. All enrolled patients in this study did not show a meaningful response to protocol
therapies. The comparison with the best protocol therapies available upon performing the
study is therefore deemed implicit, thereby justifying a self-controlled study, indirectly of
phase III.
7|Page
Section 2.0 - Synopsis
SYNOPSIS
Name of
Sponsor/Comp
any:
Name of
Finished
Product:
Name of Active
Ingredient:
Individual
Study Table
Referring to
Part
of the Dossier
Volume:
Page:
(For National
Authority
Use only)
Title of Study:
Osp. Umberto
I° Frosinone Università
degli Studi di
Roma “Tor
Vergata” .
Spontaneous
study
Osp. Umberto
I° Frosinone Università
degli Studi di
Roma “Tor
Vergata”.
Spontaneous
study.
[IRCCS]
Fondazione
Ospedale
Maggiore
Policlinico,
Mangiagalli,
Regina Elena,
Milano.
Spontaneous
study.
Policlinico
Universitario
Tor Vergata Università
degli Studi di
Roma “Tor
Vergata”.
Spontaneous
study.
Policlinico
Universitario
Tor Vergata Università
degli Studi di
Roma “Tor
Vergata”.
Spontaneous
study.
Scrambler Therapy ST-5
NA
NA
NA
NA
NA
Individual Study
Table Referring
to the Dossier
Individual Study
Table Referring
to the Dossier
Individual Study
Table Referring
to the Dossier
Individual Study
Table Referring
to the Dossier
Individual Study
Table Referring
to the Dossier
ST5 Oncology
Pain
ST5Abdominal
Cancer
ST5Neuropathic
Pain
ST5-RCT trial
Investigators:
Spaziani S,
Sabato A.F.,
Marineo G.
Spaziani S,
Sabato A.F.,
Marineo G.
Sabato AF, Gatti
A., Marineo G.
Publication
(3) (reference)
:
Artificial
neurons in
oncology pain:
the potential of
Scrambler
Therapy to
modify
biological
information.
International
Congress
Series.2003;Aug
; Vol. 1255:381388
Untreatable
pain resulting
from abdominal
cancer: new
hope from
biophysics?
JOP. 2003 Jan;
4(1):1-10.
Scrambler
therapy.
Minerva
Anesthesiol.
2005 Jul-Aug;
71(7-8):479-82.
Iorno V. ,
Gandini C.,
Moschini V.
Marineo G.
Submitted (3)
ST5Historical
data about
monitoring and
follow-up
Gatti A., Sabato
AF, Marineo G.
Scrambler
Therapy in
neuropathy
pain.
Relations at IV
and V National
Course for
Improvement
and High
Specialization in
neuropathy
pain.
Pathos.2007;
Jan.; Vol 14 (1);
99-105
8|Page
Studied period
(years): Phase
of
development:
(date of first
enrolment)
(date of last
completed)
Phase of
development:
Objectives:
Studied period
2002. Phase of
development:
18/03/2002 –
03/06/2002
Studied period
2002 (second
phase of the
previous one).
Phase of
development:
15/05/2002 –
03/06/2002
II
Studied period
2004. Phase of
development:
Historical data
base from
01/01/2004 to
31/12/2004
Studied period
2002. Phase of
development:
09/02/2004 –
27/08/2004
Studied period
2004. Phase of
development:
Historical data
base from
01/01/1999 to
31/12/2006
III (2)
III
IV
Efficiency check
in patients with
high-grade
benign chronic
pain not
responding to
other
treatments.
Safety check.
Check of
treatment
length
protocols.
Efficiency check
in patients with
high-grade
benign chronic
pain under
controlled
randomized
study. Safety
check. Check of
treatment
length
protocols.
General check of
efficiency and
safety in short
and long terms
about patients
with high-grade
benign chronic
pain not
responding to
other
treatments.
Self-controlled
(1). Unblinded
trial
Parallel study
for the selective
efficiency check
in terminal
oncology
patients with
high-grade
visceral pain not
responding to
other
treatments.
Safety check.
Check of
treatment
length
protocols.
Self-controlled
(1). Unblinded
trial
Methodology:
Self-controlled
(1). Unblinded
trial –
Prospective
study
Self-controlled
(1). Unblinded
trial –
Prospective
study
33
11
226
RCT vs
Multidrug
Therapy
(AMITRIPTYLIN
E+
OXYCODONE +
CLONAZEPAM).
Two-armed
control study.
Unblinded trial
.Prospective
study
52
Number of
patients
(planned and
analyzed):
Diagnosis and
main criteria
for inclusion:
Terminal phase
cancer
(palliative
cures),
extremely high
pain, drugresistant pain
Terminal phase
cancer
(palliative
cures),
extremely high
visceral pain,
drug-resistant
pain
High-grade
neuropathy
chronic pain
(FBBS, Lumbsc.,
PHN,
Trigeminal, Post
Surgery, Brach.
Plex, Pudendum,
Low Back Pain,
others) drugresistant
High-grade
neuropathy
chronic pain
certain/putative
(post-surgical
neuropathic
pain, postherpetic
neuralgia,
narrow canal
syndrome)
II
General
efficiency check
in terminal
oncology
patients with
high-grade pain
not responding
to other
treatments.
Safety check.
Check of
treatment
length
protocols.
9|Page
2297 (Year
1999 – 2006)
(Year 2004 2006, N=741)
High-grade
neuropathy
chronic pain
(FBBS, Lumbsc.,
PHN,
Trigeminal, Post
Surgery, Brach.
Plex,
Pudendum,Low
Back Pain,
CervicalBrachial) drugresistant
Test product,
dose and mode
of
administration
, batch
number:
Product:
Scrambler
Therapy ST5.
Dose and mode:
min. 30 - 45
minutes/day,
max. upon need
for a minimum
of 10
treatments.
Administration
mode:
disposable 5-cm
electrodes for
ECG.
Batch Number:
01 to 10
Product:
Scrambler
Therapy ST5.
Dose and mode:
min. 30 - 45
minutes/day,
max. upon need
for a minimum
of 10
treatments.
Administration
mode:
disposable 5-cm
electrodes for
ECG.
Batch Number:
01 to 10
Product:
Scrambler
Therapy ST5.
Dose and mode:
30 - 45
minutes/day,
for a minimum
of 10 and a max.
of 30 single
treatments.
Administration
mode:
disposable 5-cm
electrodes for
ECG.
Batch Number:
11
Product:
Scrambler
Therapy ST5.
Dose and mode:
45 minutes/day,
for 10 single
treatments.
Administration
mode:
disposable 5-cm
electrodes for
ECG.
Batch Number:
12
Duration of
treatment:
Biostatistic
Length: 10 basic
45-min
treatments upon
needs and
evaluation of
efficiency being
kept till natural
pathology end
point.
Biostatistic
Length: 10 basic
45-min
treatments upon
needs and
evaluation of
efficiency being
kept till natural
pathology end
point.
Ethical length:
treatment kept
till natural
pathology end
point.
In current
clinical practice,
no variation
with respect to
the protocol
used in the
study.
Ethical length:
treatment kept
till natural
pathology end
point.
In current
clinical practice,
no variation
with respect to
the protocol
used in the
study.
10 single
treatments
divided into two
blocks of 5 daily
treatments per
week, possibly
repeatable till a
max. of 3
complete cycles.
Between a
treatment week
and the
following, a
pause of a week
is foreseen.
10 single
treatments
divided into a
single treatment
a day for 5
days/week.
Global
treatment
length: two
consecutive
weeks.
In current
clinical practice,
no variation
with respect to
the protocol
used in the
study.
VAS scale,
numeric,
descriptive
simple, daily
patient diary
about 24 hours
(descriptive
scale), reduction
in the
consumption of
analgesia drugs
VAS scale,
numeric,
descriptive
simple, daily
patient diary
about 24 hours
(descriptive
scale), reduction
in the
consumption of
analgesia drugs
In current
clinical practice
on benign pain,
according to
cases the two
clinically tested
protocols are
used.
VAS scale
Reference
therapy, dose
and mode of
administration
, batch number
Criteria for
evaluation:
Efficacy:
VAS scale,
reduction in the
consumption of
analgesia drugs
10 | P a g e
Product:
Scrambler
Therapy ST5.
Dose and mode:
30 - 45
minutes/day,
for a minimum
of 10 and a max.
of 30 single
treatments.
Administration
mode:
disposable 5-cm
electrodes for
ECG.
Batch Number:
From 1999 to
2003 prototypes
under
development.
Since 2004 n.
11
10 single
treatments
divided into two
blocks of 5 daily
treatments per
week, possibly
repeatable till a
max. of 3
complete cycles.
Between a
treatment week
and the
following, a
pause of a week
is foreseen.
In current
clinical practice
on benign pain,
according to
cases the two
clinically tested
protocols are
used.
VAS scale
Criteria for
evaluation:
Safety:
Statistical
methods:
SUMMARY CONCLUSIONS
EFFICACY
RESULTS:
SUMMARY CONCLUSIONS
SAFETY
RESULTS:
Medical visit,
questionnaire
about
undesired, side
effects, global
subjective
impressions,
also referred to
“particular”
sensations that
cannot be better
described.
Medical visit,
questionnaire
about
undesired, side
effects, global
subjective
impressions,
also referred to
“particular”
sensations that
cannot be better
described.
Paired t-test
Paired t-test
Extremely
efficient
regarding
clinical
significance and
statistical
significance.
No undesired
side effect has
been pointed
out or reported.
Optimum
compliance
Extremely
efficient
regarding
clinical
significance and
statistical
significance.
No undesired
side effect has
been pointed
out or reported.
Optimum
compliance
Medical visit
during
treatment and
follow-up,
questionnaire
about
undesired, side
effects, global
subjective
impressions,
also referred to
“particular”
sensations that
cannot be better
described.
Paired t-test
Extremely
efficient
regarding
clinical
significance and
statistical
significance.
No undesired
side effect has
been pointed
out or reported
during
treatment or
upon following
control visits.
Optimum
compliance
Medical visit
during
treatment and
follow-up,
questionnaire
about
undesired, side
effects, global
subjective
impressions,
also referred to
“particular”
sensations that
cannot be better
described.
One-way
Analysis of
Variance
(ANOVA) and
Tukey-Kramer
Multiple
Comparisons
Test. Gaussian
distribution was
analyzed with a
normality test of
Kolmogorov and
Smirnov, which
gave a positive
result.
Extremely
efficient
regarding
clinical
significance and
statistical
significance.
No undesired
side effect has
been pointed
out or reported
during
treatment or
upon following
control visits.
Optimum
compliance
11 | P a g e
Medical visit
during
treatment and
follow-up,
questionnaire
about
undesired, side
effects, global
subjective
impressions,
also referred to
“particular”
sensations that
cannot be better
described.
Paired t-test
Extremely
efficient
regarding
clinical
significance and
statistical
significance.
No undesired
side effect has
been pointed
out or reported
during
treatment or
upon following
control visits.
Optimum
compliance
SUMMARY CONCLUSION:
Date of the
report:
The method is
an important
resource for
pain therapists
that have to
treat cases not
responding to
other types of
treatment.
Safety-related
data are aligned
with theoretical
expectancies
and what is
known in
scientific
reference
literature about
effects of very
low-intensity
electric
stimulation.
The method is
an important
resource for
pain therapists
that have to
treat cases not
responding to
other types of
treatment.
Safety-related
data are aligned
with theoretical
expectancies
and what is
known in
scientific
reference
literature about
effects of very
low-intensity
electric
stimulation.
The method is
an important
resource for
pain therapists
that have to
treat cases not
responding to
other types of
treatment.
Safety-related
data are aligned
with theoretical
expectancies
and what is
known in
scientific
reference
literature about
effects of very
low-intensity
electric
stimulation.
The method is
an important
resource for
pain therapists
that have to
treat cases not
responding to
other types of
treatment.
Safety-related
data are aligned
with theoretical
expectancies
and what is
known in
scientific
reference
literature about
effects of very
low-intensity
electric
stimulation.
The method is
an important
resource for
pain therapists
that have to
treat cases not
responding to
other types of
treatment.
Safety-related
data are aligned
with theoretical
expectancies
and what is
known in
scientific
reference
literature about
effects of very
low-intensity
electric
stimulation.
29/01/2009
29/01/2009
29/01/2009
29/01/2009
29/01/2009
Notes:
1) The severity grade of pain in enrolled patients did not ethically allow the treatment with a
placebo. All enrolled patients did not show a meaningful response to protocol therapies,
thereby justifying a self-controlled study. The comparison with the best protocol therapies
available upon performing the study and with reference scientific literature is deemed
implicit.
2) A phase III study must be directly compared with the best protocol treatments used at that
time. All enrolled patients in this study did not show a meaningful response to protocol
therapies. The comparison with the best protocol therapies available upon performing the
study is therefore deemed implicit, thereby justifying a self-controlled study, indirectly of
phase III.
3) These clinical studies were performed without involvement from the manufacturers or
sponsors, therefore without the chance of a biasing the results of the clinical studies. Taking
into account the strong clinical and social relevance of data emerging from studies, it has
ethically been established to minimize the scientific publications, till a large-scale industrial
production and a capability of broad commercialization which will support all requests of use
normally deriving from scientific publications with high awareness.
12 | P a g e
Section 3.0 - Table of contents for the individual clinical study report
Individual Study Table Referring to the Dossier
Section 4.0 - List of abbreviations and definitions of terms
IRCCS: Istituto di Ricovero e Cura a Carattere Scientifico (excellent hospital structure enabled
for health performance and scientific research)
BrachPlex: Brachial Plexus Neuropathy
FBSS: Failed Back Surgery Syndrome
LBP: Low Back Pain
Lumbsc: Lumbar and Sciatic Pain
NRS: Numerical/Numeric Rating Scale
PHN: Post-Herpetic Neuralgia
Post Surg.: Post Surgical
PSNP: Post-Surgical Neuropathic Pain
RCT: Randomized Clinical Trials
SCS: Narrow Canal Syndrome
TENS: Transcutaneous Electrical Nerve Stimulation
TRIGEM: Trigeminal Neuralgia
VAS: Visual Analogue Scale
VRS: Verbal Rating Scale
13 | P a g e
Section 5.0 - Overall Study Design and Plan: Description
Note: Specific data about studies described below are available in appendixes 16.1.1 and
16.1.2.
Study Title: “Scrambler ST5- Oncology Pain” and “Scrambler ST5-Abdominal Cancer Pain“
This study was performed to evaluate use of the Scrambler ST5 in chronic intractable pain
from an oncological condition during a terminal illness. The study was an “unblinded selfcontrolled” study that included patients that presented with a lack of response to other
therapies and a very high Visual Analog Pain Scale. Further selection criteria only dealt with
exclusion of patients with neuro-lesion surgical interventions that could interfere with result
evaluations and possible incompatibility with precautionary contra-indications typical of
TENS
In the first phase (ST5- Oncology Pain), treatment effects were observed on different types of
cancer patients in their terminal phase, to evaluate safety, efficiency, compliance and
optimum treatment mode. In the second phase, the study focused on visceral pain associated
with oncology which is difficut to manage due to the intensity of the pain.
The primary effectiveness endpoint is immediate pain relief during the treatment during a
cycle of 10 treatments. The secondary effectiveness endpoint is the decrease in the use of
analgesic drugs. Due to humanity reasons, the treatment was continued beyond the period of
10 treatments, until the patients expired. This allowed a preliminary determination, within
the parameters of the study, that patients did not develop a resistance to treatments as
compared to other less efficacious therapies.
Study Title:” ST5-Neuropathic Pain”, “ST5-Historical data about monitoring and follow-up”
This study was performed to evaluate use of the Scrambler ST5 during neuropathy pain
treatment that did not respond to other treatments. This study was an unblinded selfcontrolled trial that was a prospective study with the same evaluation protocol as the one
above. The most important difference between this study and the oncological study was in
the follow up time which was not possible with the terminal phase oncology patients.
Patients were evaluated at a minimum of 3 months after completion of the treatment cycle.
.
Historical data for the Scrambler ST5 has been compiled from 1999 to 2006. This extensive
time frame allows for a complete evaluation of the safety and efficacy for the Scrambler ST5.
The technology of Scrambler ST5 was also evaluated. The technology from the functional
point of view was designed in 2002. After the positive oncological results, the design was
frozen and the results historically evaluated since 2004.
14 | P a g e
During the development period of 1999 to 2003 it was determined that within a single
therapeutic cycle (10 treatments) 2.97 cycles were necessary to obtain the best result for pain
relief. However, after slight technological changes to the Scrambler ST5, in 2003), 2.09 cycles
were needed for pain relief. After 2004 onwards, averages of 1.2 cycles (12 single treatments)
were used evaluated to be most effective for pain relief.
Study Title: ST5-Randomized Controlled Trial (RCT)
The RCT study was performed to confirm the safety and effectiveness of the historical data
studies. The treatment protocol of this RCT required a 10 treatment regimen. The clinical
studies conducted for oncology-based pain provided a basis for a treatment protocol and
strategy to focus on efficacy for monitoring benign pain after completion of a regimen and
observed reoccurrence of pain. Currently, the mean length of a treatment cycle is based on
defined safety parameters for patient care and, independently determined from the tested
protocol, is 10/12 single applications, as well as the observed absence of side or undesired
effects.
The “ST5-RCT trial” study incorporated administering of an efficient therapy and optimized
treatment protocol as a control arm which was based on a combination of
amitriptyline/oxycodone/clonazepam,
Section 5.1 - Changes in the Conduct of the Study or Planned Analyses
No changes to be reported.
15 | P a g e
Section - 6.0 Disposition of Patients
Self-controlled studies
Since these are not RCT studies, the arrangement of patients was simply performed in a
chronologic order depending on the appearance of the following general conditions:
1. High-grade pain not responding to other treatments being used at that time
2. Met the inclusion/exclusion criteria
The following table describes the study recruitment:
Study title
ST5- Oncology Pain
Pathologies
Oncology pain
ST5-Abdominal
Cancer
Oncology visceral pain
ST5-Neuropathic Pain
Neuropathic pain
ST5-RCT trial
Neuropathic pain
Inclusion Criteria
Oncology pain not
responding to other
protocol treatments.
VAS>=7. Terminal
patients.
Oncology - visceral pain
not responding to other
protocol treatments.
VAS>=7. Terminal
patients.
Benign neuropathic pain
not responding to other
protocol treatments.
VAS of a high grade (typ.
>=6)
-Presence
of
neuropathic pain.
-VAS pain intensity > 6
in the Failure to respond
to currently used drug
treatment
of
neuropathic pain (use of
antidepressants,
anticonvulsants
preceding three months
and opioids for a period
of at least 6 months),
absence of significant
responses to TENS or
other similar electro
analgesic methods.
In addition to pain,
presence of related
sensitive
symptoms:
allodynia, hyperpathy,
hyperesthesia. Presence
of pain for at least 6
months
Frequency of pain > 4
days per week.
16 | P a g e
Exclusion Criteria
Pacemaker, neurolesions for controlling
pain.
Pacemaker, neurolesions for controlling
pain.
Pacemaker, neurolesions for controlling
pain.
Pacemaker,Cancerrelated pain,Presence
of serious psychiatric
disorder
(schizophrenia, manicdepressive psychosis,
primary
major
depression).
ST5-Historical
Neuropathic pain,
monitoring under
development and since
2004 post European
authorization
Benign neuropathic pain
not responding to other
protocol treatments.
VAS of a high grade (typ.
>=6)
Pacemaker, neurolesions for controlling
pain.
RCT study
The study utilized two arms as follows:
(A) The pharmacological therapy being used has been replaced with the most recent update
available in International guidelines, adapting the dosage to patient needs. The control arm
received what is considered a more efficacious multidrug therapy consisting of
amitriptyline/oxycodone/clonazepam.
This replaced the initial treatment of
amitriptyline/gabapentin/tramadol (all recruited patients were initially on this MDT).
(B), the Scrambler group, due to ethical reasons, were kept on the initial MDT from the
recruitment phase and did not receive any modification to the pharmacological therapy as in
the control arm (A). . Arm (B) received the initial MDT treatment with the Scrambler Therapy
for a complete cycle ten (10) 45-min therapies in two weeks with daily treatment from
Monday to Friday). The initial MDT component of the therapy was reduced where feasible
according to patient response to the Scrambler treatment, and computing biostatistically the
drug change by type and dose.
Randomization was performed after the inclusion/exclusion criteria were met. The
randomization of the two arms of the study took place alternately on a basis of the
characteristics of the diagnosis type, pain intensity and similarity of the pharmacological
protocol in use at the time of recruitment. As stated above control arm A replaced the initial
multidrug therapy with the more efficacious multidrug therapy based on scientific knowledge.
The arm B received the treatment with the Scrambler Therapy ST5 and maintained the old
multidrug protocol, in order to avoid mistakenly attributing the benefits of the ST5 treatment
from the variation of drugs.
17 | P a g e
Patient Tree
ST5- Oncology Pain
N=33
ST5-Abdominal
Cancer N=11
ST5Neuropathic Pain
N=226
ST5-Historical
N=2297
(Year 2004-2006,
N=741)
Medical visit for enrolment check.
Patient excluded
from the study
Inclusion
criteria met?
Start treatment with
Scrambler Therapy ST5
(10 therapies in two
weeks)
ST5- Oncology Pain N= 33 completed
ST5-Abdominal Cancer N= 11 completed
ST5-Neuropathic Pain N= 204 completed
ST5-Historical N= 2068 completed
ST5- Oncology Pain N= 0 withdrawn
ST5-Abdominal Cancer N= 0 withdrawn
ST5-Neuropathic Pain N= 22 withdrawn (1)
ST5- Historical N= 229 withdrawn (1)
(1) no responders
18 | P a g e
Arrangement of RCT Patients
Medical visit for enrolment check. N =
52 included, divided into two
homogeneous groups by pathology,
pain intensity and cures used upon
recruiting
Inclusion
criteria
compatible?
Patient excluded
from the study
Has the patient similar
characteristics wih a
patient in group A not
present in group B ?
Yes
Start treatment with
Scrambler Therapy ST5
(10 therapies in two
weeks)
N=26
completed
Case necessary to
complete group
A?
Yes
Start continuous treatment
with new pharmacologic
therapy (AMITRIPTYLINE +
OXYCODONE +
CLONAZEPAM).
N=26
completed
N=0
withdrawn
19 | P a g e
N=0
withdrawn
Important note about enrolment criteria.
It is generally required practice to count the number of patients that have not been included
in the study during the preliminary enrollment. . In the types of studied patients, the primary
selection criteria have been the lack of response to protocol therapies and very high VAS
levels. Patients not enrolled due to not meeting the selection criteria have not been counted.
Statistically, the enrolment criteria on a probabilistic basis would have produced a very high
number of rejects due to not enough high VAS, partial efficacious response to drug therapies,
and low clinical significance level due to the critical objectives posed by the studies. For these
reasons, it has been determined not practical to count the number of patients not included in
the study. It is clearly evident that the selection has been performed towards identifying the
limited cases that are highly challenging in the clinical practice. Consequently, the ratio
between patients meeting the criteria and rejected patients would statistically favor the
rejected patients.
Section 7.0 - Safety evaluation
General effects of exposure to electric current
The general risk linked to the circulation of electric currents in the human body is evaluated
depending on intensity of the current that passes through it. This parameter is linked to
relationship I=V/R, where I means the circulating current, V the applied voltage, R the
resistance (impedance) of the human body.
The physical-pathologic effects of current on a human body have been studied starting from
1960 by Dalziel. Afterwards, in 1977, Bieglemeier improved these studies, pointing out the
relationships between current intensity and effect on man and woman due to prolonged
exposures and continuous stimulations. These studies refer to low-frequency alternate
current from electric mains. No meaningful differences in results have been observed
between stimulations at 50 Hz and 60 Hz.
Threshold/effect relationships
The identified starting threshold of perception of electric stimulus (mean values) is 1.1 mA in
men and 0.7 mA in women. The threshold at which effects start to be produced on muscular
contraction is included between 10 and 20 mA. After having exceeded this threshold, the
muscle contraction starts losing the voluntary control of the subject exposed to stimulation.
Thresholds below 20 mA are generally deemed not dangerous, below 10 mA completely
innocuous.
In conventional transcutaneous electrical nerve stimulation, there are generally very high
peak currents, exceeding 20 mA, but with a time length shorter than l mS. It is further possible
to operate in a wider frequency range than the electric mains, typically included between 1
and 150 Hz. The limited length of the current peak allows obtaining a mean delivery value
that falls within the safety limits for human health.
For this reason, in electrial stimulation it is preferable to take into account the electric current
effects by comparing current intensity with pulse length time. A further evaluation can be
20 | P a g e
performed by taking into account how many pulses are delivered in one second, namely by
mutually linking current intensity, pulse length, stimulation frequency. The results are
expressed in sub-multiples of a Coulomb, the electric force measure unit.
It is then possible to re-write data obtained by Bieglemeier (important international standard
reference), that can be analytically identified as critical safety thresholds for a prolonged
exposure, in the form normally used to evaluate the electric force applied on men by a TENS.
Single Pulse 50 Hz
200 µC
Single Pulse 50 Hz
400 µC
10 mA
Continuous
Single Pulse 60 Hz
Stimulation 50 Hz
10000 µC/Sec
166 µC
20 mA
Continuous
Single Pulse 60 Hz
Stimulation 50 Hz
20000 µC/Sec
333 µC
Continuous
Stimulation 60 Hz
10000 µC/Sec
Continuous
Stimulation 60 Hz
20000 µC/Sec
The medical device under consideration operates between 43 and 52 Hz. The following data
have been measured on a standard 500 ohm load.
 mean delivered current <3 mA under any condition
 peak delivered current < 5.5 mA under any condition
 mean electric force in single pulse: 38.3 µC, with a peak of 49.5 µC at 43 Hz (2128.5
µC/S), and a peak of 44.1 µC (2293 µC/S) at 52 Hz.
In general, these values, in addition to falling within the safety limits measured by Bieglemeier
for a prolonged exposure, are similar or with less intensity with respect to the majority of
authorized TENS for commercialization. The maximum time of a single treatment is fixed by a
timer adjustable between 20 and 60 min. The maximum stimulation time is also aligned on
common values.
The really meaningful differences with a traditional TENS device are the functional
waveforms. In traditional TENS, usually square waves are used, capable of generating, on a
500 ohm load, maximum currents included between 120 - 200 mA for periods of time shorter
than 1 mS.
In the requested device, waveforms are used with soft rise and fall edges, and variable pulse
length times included between 8 - 20 mS. The type of used waveform therefore allows a less
traumatic stimulation, gradually dividing in time currents whose intensity is very low, both as
mean and as peak values.
At experimental level, these analytic remarks find their confirmation in the optimum
compliance shown by patients, even in treating areas that are particularly sensitive to electric
stimulations.
21 | P a g e
It has further been observed that the typical reddening visible after stimulation under the
area in which electrodes have been placed, is minimal, generally lower than the one observed
in conventional stimulations.
Typically, a treatment is from 30 to 45 minutes long. In rare cases, it has been necessary to
extend the concluded treatment by repeating it. In the repetition, no meaningful variations of
compliance have been observed, or other risk elements deriving from the increased exposure
time.
A Scrambler ST5 treatment cycle for benign chronic pain lasts for 10/12 applications with a
preferably daily frequency.
During oncology pain, treatment is provided according to patient needs. After the first 10/12
treatments, in the majority of cases a single treatment every 24 hours or more is adequate to
control or reduce pain. In a small number of cases, more than one treatment a day is required.
Distribution of the patients according to the mean duration of absence of pain after each
single application.
During this study, no adverse or undesired effects were observed. As with most TENS
devices, after frequent use, symptoms of skin irritation can be observed and can be resolved
by moving the electrodes.
22 | P a g e
Other remarks
During clinical studies or in services to public delivered by public hospitals, such as in the
stable active phase-IV monitoring in the Policlinico Universitario di Tor Vergata (Department
Of
Intensive
Care,
Pain
Medicine
and
Anesthesiology,
http://www.ptvonline.it/uo_ter_ant_ing.asp ), no side or undesired effects have ever
occurred. Policlinico di Tor Vergata carefully monitors over 400 cases every year (so far
globally more than 3000 cases), that are progressively added to already document knowledge.
The contraindications in the device manual are only due to precautionary principles, and not
to experimental observations. These precautionary principles have suggested to list, as
contraindications of a preventive character, all those that are generally used in electrical
stimulation devices.
Section 8.0 - Discussion and overall conclusions
The purpose of this clinical study was to evaluate the safety and effectiveness of the
Scrambler ST5 during use in chronic intractable pain that was not responsive to other types of
pharmacologic or electrical stimulation therapies. For this reason, all studies have included
the lack of responsiveness to other therapies as inclusion criteria in the protocol.
Remarks about study method and Placebo effect evaluation
The particular type of medical device examined intrinsically prevents a reliable double-blind
study. The remaining choices could be addressed towards blind studies with placebo device,
or towards a control (or self-control) group with therapies deemed surely efficient. This latter
option has been chosen, following considerations that first of all are ethical, and secondary
analytical about known placebo effects. The ethical question deals with the presumable
prolonged sufferance in the group treated with a placebo device, that cannot be justified due
to pain severity that can be found in patients enrolled in the studies.
The analytical support question does not allow an exact evaluation of the incidence of a
placebo in studies shown in support of the request for authorization to commercialization, but
anyway allows defining highly probable thresholds of a maximum placebo effect that can be
assumed depending on what is known from scientific literature about chronic pain of a high
grade.
Several scientific literature have been examined, selecting the one that best represents the
examined problem.
A study about different non-pharmacological therapies (Chou R, Huffman LH; Nonpharmacological therapies for acute and chronic low back pain: a review of the evidence for
an American Pain Society/American College of Physicians clinical practice guideline) that
require a strong (also physical) interaction of a therapist with a patient, shows that, in acute
and chronic pain (Low Back Pain), the influence of the placebo effect is limited, and does not
23 | P a g e
exceed 2 points on an evaluation scale standardized from 0 to 10. The detected placebo effect
is transient, prevailing in acute pain, and ends in a very short range of time.
A double-blind study about diabetic neuropathy with TENS (Forst T, Nguyen M, Forst S,
Disselhoff B, Pohlmann T, Pfützner A. Impact of low frequency transcutaneous electrical nerve
stimulation on symptomatic diabetic neuropathy using the new Salutaris device. Diabetes
Nutr. Metab. 2004 Jun;17(3):163-8) shows the absence of variations in the placebo group in
re-evaluating pain intensity after six weeks.
Other pharmacological studies on a wide population in double-blind towards a placebo in
neuropathy chronic pain, include very low incidences of pain reduction in the placebo group
(Ex. Rowbotham M et alt. Gabapentin for the treatment of post-therapeutic neuralgia: a
randomized controlled trial. JAMA. 1998 Dec 2;280(21):1837-42.), often at detection limit.
In general, these explicative data surely point out the existence of a placebo effect in treating
chronic pain, but generally this effect has scarce or null clinical meaning, especially if reevaluated after one month or more.
These data that derive from scientific literature agree with ethical indications that suggest to
avoid recurring to a placebo when treating chronic pain.
In conclusion, due to what appears from the most important scientific literature about this
subject, the analytic incidence of the placebo effect within the performed studies has scarce
clinical importance, and does not substantially modify the interpretation of obtained clinical
results.
Remarks about efficiency and safety of results of studies.
The obtained results can be quickly evaluated by observing Section 9.0, which points out the
relevant clinical importance in the examined pain context. This clinical importance is
supported by the statistical significance associated to every study.
Since this is a non-invasive therapy free from toxicity, the risk/benefit ratio is surely
favorable.
Small/medium-term follow-up of single studies, like long-term ones for phase-IV studies and
more, confirm the theoretical forecasts and the general know-how about electrical
stimulation with absence of side or undesired effects. Moreover, the absence of resistance to
treatment appears, in its cyclic repetitions where it had been necessary.
In conclusion, the device for which an authorization to commercialization is requested, both
from the theoretical and from the experimental evidence, shows an extremely high degree of
safety and absence of side or undesired effects.
The usefulness of the device in support of pain therapists is particularly evident, where they
need efficient outcomes where other treatments fail or generate insufficient results.
24 | P a g e
Remarks about oncology pain
In case of oncology pain in the terminal illness phase, a treatment protocol according to needs
of the patient must be taken into account.
The used biostatistics refer to immediate patient needs taking into account his reduced life
expectancy.
Regarding this, in phase-II studies, even if performed on a reduced number of cases, a relevant
statistical significance and clinical significance of the results clearly appear.
These data are particularly meaningful regarding social-health aspect of palliative cures.
Analytically, it is possible to note that the most difficult component to be treated with
25 | P a g e
traditional protocols, even in oncology pain, is always the neuropathy component. Typical
and more frequent neuropathy pain complications for the oncology pain deal with;
compression and invasion of nervous structures, toxic neuropathies from chemotherapy,
radiotherapy, surgical intervention.
Regarding this, the performed studies on benign chronic pain, though not being specifically
aimed to oncology pain, are evidential support.
Independent studies on a wider population will be presumably favored when
commercializing the method.
Section 9.0 - Tables, figures and graphs referred to but not included in the text
The following information may be presented in this section of the core clinical study report:
Section 9.1 - Demographic Data Summary figures and tables.
Demographic Data Summary
Study title
ST5Oncology
Pain
ST5Abdominal
Cancer
ST5Neuropathic
Pain
ST5-RCT
trial
ST5Historical
(2004-2006
Phase IV)
Mean age
M
F
Tot.
65.5 (SD
12.09)
15
18
33
60.2 (SD
12.3)
3
8
11
62.11 (SD
14.93)
94
132
226
53.34 (SD
16.14)
19
33
52
451
N=741
(Year 1999 –
2006,
N=2297)
62.73 (SD
13.78)
290
26 | P a g e
Section 9.2 Efficacy Data Summary figures and tables (data and graphs not included in
other parts of the text).
ST5- Oncology Pain: 10 treatments for stabilization (10 days). Ethical treatment
maintenance upon need till natural illness conclusion (variable length).
ST5-Abdominal Cancer: 10 treatments for stabilization (10 days). Ethical treatment
maintenance upon need till natural illness conclusion (variable length).
27 | P a g e
ST5-Neuropathic Pain: 10 basic treatments/week. One suspension week every treatment
week. Max. six global treatment weeks. Currently this protocol has to be deemed passed. The
protocol developed in parallel from 2004 on, that provides for 10/12 treatments in two
consecutive weeks (without intermediate pauses), in studies about oncology pain and in RCT
on benign pain, like in hospital clinical practice, seems to guarantee better results in the short
and medium/long term. The global response of responder patients (Pain relief >=50%) is
80.09 %, that of partial responder patients (Pain relief from 25% to 49%) is 10.18%. The
length of the analgesic response changes on average from 1 to 3 months or more in responder
patients. In recall cycles, where necessary, no developments of resistance to treatment have
been observed.
28 | P a g e
ST5-RCT trial. VAS for total (26+26) number of patients. The complex variation valued with
One-way Analysis of Variance (ANOVA) shows statistical significance (P<0.0001). The
comparison between the two study arms at equal evaluation intervals through the TukeyKramer Multiple Comparisons Test confirms this significance (P<0.001).Basic statistical
references were applied starting from beginning (T0) of study protocol, before therapy
change. The following references are taken for every group at 1 (T1), 2 (T2) and 3 (T3)
months from variation for follow-up observations. Immediately after evaluation at T0, only
the expected ST cycle was applied in the treatment arm (45 minutes every 10 days, 1
treatment per day, 5 times a week). Likewise, immediately after evaluation at T0, the control
arm received the new pharmacological treatment expected in the protocol. Evaluations
pertain to VAS pain intensity, allodynia presence and drug consumption.
29 | P a g e
PSNP
PHN
SCS
ST5-RCT trial. VAS trends by class of diagnosis: post-surgical neuropathic pain (P< 0.0001),
post-herpetic neuralgia (P< 0.0001), narrow canal syndrome (P= 0.0108).
30 | P a g e
ST5-RCT trial. VAS trends T3 ST by neuropathic class (monoradicular neuropathies,
pluriradicular neuropathies).During data analysis, when VAS analysis was stratified for
monoradicular or pluriradicular pain, it was observed that pain reduction was more
pronounced both at the end of treatment and after three months in patients of the group
treated with Scrambler Therapy suffering from monoradicular pain. In particular, analysis of
variance (Tukey-Kramer Multiple Comparisons Test) revealed elevated statistical significance
(P<0.001) in the direct comparison at T3 between mono and pluriradicular pain in the ST
treatment group. The same verification in the control group has no statistical significance
(P>0.05).
31 | P a g e
ST5-RCT trial. Percentage presence of allodynia at the statistical reference times. Allodynia
was present at the time of inclusion in 19 (73.07%) patients of the control group and 20
(76.92%) of the treated group. At T1, allodynia is present in 9 (34.61%) patients in the
control group and in none in the treated group. At T3 the number of patients presenting
allodynia increased to 11 (42.30%) in the control group, 4 (15.38%) in the treated group. The
statistical significance between the two groups was valued by Fisher's Exact Test (T1 ctrl vs
T1 st P=0.0017, T2 ctrl vs T2 st P= 0.0094, T3 ctrl vs T3 st P= 0.0644).
32 | P a g e
Antidepressants
Opioids
Anticonvulsivant
ST5-RCT trial. Variation of analgesic consumption by type (antidepressants, anticonvulsants,
opioids) in the group treated with Scrambler Therapy. Average dosage taken at T0 is initially
considered equal to 100%, and subsequent percentage variations at T2 and T3 (P<0.0001)
are considered of major clinical significance for dosage adjustment. Dosage reduction was
applied only in ST treated patients whose pain intensity did not increase in response to the
pharmacological modification. At T3 opioids are totally eliminated in 11 cases out of 17,
halved in 1, unvaried in 5. Anticonvulsants were eliminated in 17 cases out of 24, reduced in
1, unvaried in 6. Lastly, antidepressants were eliminated in 9 cases out of 19, reduced in 4 and
unvaried in 6. Dosage variation showed statistical significance (repeated ANOVA measures:
P<0.0001) in all examined cases.
33 | P a g e
Section 9.3 - Safety Data Summary figures and tables.
Safety Data Summary
Study title
ST5Oncology
Pain
ST5Abdominal
Cancer
ST5Neuropathic
Pain
ST5-RCT
trial
ST5Historical
Cutaneous
lesions
Ipoanesthesia
Paresthesies
Disesthesies
Other
(specify)
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
N=0
9.3.1 Displays of Adverse Events
Nothing to report
9.3.2 Listings of Deaths, Other Serious and Significant Adverse Events
Nothing to report
9.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse
Events
Nothing to report
9.3.4 Abnormal Laboratory Value Listing (each patient)
Nothing to report
34 | P a g e
Section 10.0 - Protocol and protocol amendments
Protocol
Study and
Typology
ST5Oncology
Pain. Selfcontrolled.
Unblinded.
Prospective
study
ST5Abdominal
Cancer. Selfcontrolled.
Unblinded.
Prospective
study
ST5Neuropathic
Pain. Selfcontrolled.
Unblinded.
Prospective
study
Follow-up
min.
Due to ethical
reasons,
patients have
been
followed till
the natural
end of
pathology
Due to ethical
reasons,
patients have
been
followed till
the natural
end of
pathology
3 months
Inclusion
Criteria
Oncology
pain not
responding
to other
protocol
treatments.
VAS>=7.Term
inal patients.
Oncologyvisceral pain
not
responding
to other
protocol
treatments.
VAS>=7.Term
inal patients.
Benign
neuropathy
pain not
responding
to other
protocol
treatments.
VAS of a high
grade (typ.
>=6)
Exclusion
Criteria
Pacemaker,
neuro-lesions
for
controlling
pain.
Primary
Variable
VAS Variation
Secondary
Variables
Drug
consumption
variation
Pacemaker,
neuro-lesions
for
controlling
pain.
VAS Variation
Drug
consumption
variation
Pacemaker,
neuro-lesions
for
controlling
pain.
VAS Variation
35 | P a g e
N min=
30
Success
Endpoints
Pain relief >=
50% in at
least 70% of
cases
10
Pain relief >=
50% in at
least 70% of
cases
1-year
window
(review)
Pain relief >=
50% in at
least 70% of
cases
ST5-RCT
Trial.
Unblinded.
Prospective
study
3 months
ST5Historical
Monitoring
and Followup Data.
Selfcontrolled.
Unblinded.
Prospective
study
3 months
Presence of
mainly
certain
or
putative
neuropathic
pain.VAS pain
intensity > 6
in the Failure
to respond to
currently
used
drug
treatment of
neuropathic
pain (use of
antidepressa
nts,
anticonvulsa
nts preceding
three months
and opioids
for a period
of at least 6
months),
absence
of
significant
responses to
TENS
or
other similar
electroanalgesic
methods.
In addition to
pain,
presence of
related
sensitive
symptoms:
allodynia,
hyperpathy,
hyperesthesi
a. Presence of
pain for at
least
6
months
Frequency of
pain > 4 days
per week.
Benign
neuropathy
pain not
responding
to other
protocol
treatments.
VAS of a high
grade (typ.
>=6)
Pacemaker,C
ancer-related
pain,Presenc
e of serious
psychiatric
disorder
(schizophreni
a,
manicdepressive
psychosis,
primary
major
depression).
VAS Variation
Drug
consumption
variation,
allodynia.
Pacemaker,
neuro-lesions
for
controlling
pain.
50
Pain relief >=
50% in at
least 70% of
cases
8-year
window
(review)
Pain relief >=
50% in at
least 70% of
cases
Protocol amendments
No variation to report
Section 10.1 - Sample case report forms (unique pages only)
The studied treatment is categorized by definition in the TENS category. The dosing criteria
used in pharmacology is described below as treatment length in minutes.
36 | P a g e
Study Title
Length of a
single treatment
(min.)
Length of a
treatment cycle
(total number
treatments)
Administration
mode
Primary
efficiency
variable
evaluation
Secondary
efficiency
variable
evaluation
Primary safety
variable
evaluation
Secondary
safety variable
evaluation
Minimum
foreseen
Follow-Up type
Scrambler Therapy ST5 – Administration mode
ST5- Oncology
ST5ST5ST5-RCT Trial
Pain
Abdominal
Neuropathic
Cancer
Pain
45
45
30-45
45
ST5-Historical
Monitoring and
Follow-up Data
30-45
10
10
5-30
10
5-30
Disposable 5-cm
surface
electrodes
(ECG).
Disposable 5-cm
surface
electrodes
(ECG).
Disposable 5-cm
surface
electrodes
(ECG).
Disposable 5-cm
surface
electrodes
(ECG).
Disposable 5-cm
surface
electrodes
(ECG).
VAS
VAS
VAS
VAS
VAS
- Drug
consumption
variation
- Drug
consumption
variation
Medical visit
with daily check
before and after
every treatment.
General patient
subjective
impressions
recorded in
questionnaires
and daily diary
The patient due
to ethical
reasons is
constantly
assisted till the
natural
pathology
conclusion even
after the
reference
statistic cycle.
Medical visit
with daily check
before and after
every treatment.
General patient
subjective
impressions
recorded in
questionnaires
and daily diary
The patient due
to ethical
reasons is
constantly
assisted till the
natural
pathology
conclusion even
after the
reference
statistic cycle.
Medical visit
with daily check
before and after
every treatment.
Follow-Up visits
or anticipated
visits upon
patient’s
request
- Drug
consumption
variation,
allodynia.
Medical visit
with daily check
before and after
every treatment.
Follow-Up visits
or anticipated
visits upon
patient’s
request
Medical visit
with daily check
before and after
every treatment.
Follow-Up visits
or anticipated
visits upon
patient’s
request
During
treatment: reevaluation after
one week from
end of previous
block. At the end
of the treatment
cycle;
reevaluation 1, 2
and 3 months
after the end of
the
complete
cycle
After 1, 2 and 3
months from
the end of the
treatment cycle.
37 | P a g e
During
treatment: reevaluation after
one week from
end of previous
block. At the end
of the treatment
cycle;
reevaluation 1, 2
and 3 months
after the end of
the
complete
cycle
Study Title
N. Patients
Studied
population
Population of studied patients and number of patients to be include.
ST5ST5ST5- Oncology
Abdominal
Neuropathic
ST5-RCT Trial
Pain
Cancer
Pain
33
11
226
52
Oncology pain
of a high grade
in terminal
illness phase,
not responding
to other
treatments
Oncology/viscer
al pain of a high
grade in
terminal illness
phase, not
responding to
other
treatments
Neuropathy
pain of a high
grade not
responding to
other protocol
treatments
Neuropathy
pain of a high
grade not
responding to
other protocol
treatments
(typically
amytryptiline+g
abapentin+tram
adol)
ST5-Historical
Monitoring and
Follow-up Data
2297 (Year
1999 – 2006)
[N=741, Year
2004-2006]
Neuropathy
pain of a high
grade not
responding to
other protocol
treatments
Blinding / masking level and method
The first assumption of a clinical study that must provide clear results is always performing a
double blind or blind with at least one control arm. A study of this type has a value only if the
blind cannot be involuntarily unmasked. In case of current studies, it was not possible to keep
the necessary blinding level for the objective reasons that are included below.
Objective obstacles to blind/ double blind
The control arm of a blind/double blind in case of pains of a very high grade, like the one of
patients enrolled in studies, due to ethical reasons, must take into account the best therapy
deemed efficient and available during the study. This ethical interpretation, widely shared in
clinical practice, is particularly constraining when relatively long periods or observation are
foreseen and/or there are particularly severe cases like those enrolled in current studies. In
studied pain types, the best possible therapy, surely efficient and emerging from scientific
literature data, has always been of the pharmacological type. It is de facto impossible to keep
blinding by comparing a medical device with a pharmacological therapy.
Another problem that cannot be solved deals with a peculiar method characteristic, that
guarantees a high reproducibility of data, but is at the same time strongly penalizing for
blinding. As regards data reproducibility, this is ensured by the method that is wholly
controlled by a proprietary algorithm. This algorithm does not require any parametric choice
from a physician that performs the treatment, apart from setting the administration time,
standardized to 30 or 45 minutes in the studies.
The residual depending operator variable deals with the choice of dermatometers useful for
the treatment. To reduce the influence of operator training, 3 standardized reference schemes
have been developed. The choice of a scheme depends on the immediate response of the
patients. When the choice is correct, there is an immediate and complete pain disappearance
during stimulation, independently from the VAS preceding the treatment start and the type of
treated pathology.
38 | P a g e
This immediate feedback (the analgesic response is in real time with the beginning of the
stimulation) further reduces the dependent operator variability, but makes the device easily
identifiable.
Remedies adopted to compensate for the lack of blinding
To favor the clarity of the study results without blinding, alternative safety elements have
been analytically studied, that, used theoretically as a whole, should guarantee clarity of
results similar to blinding.
To obtain this, it has been decided, as a general principle, to adopt measures whose
foreseeable error rate would exclusively have implied a sub-estimation of the real efficiency
of the Scrambler Therapy, never the reverse, In this way, a trend has been adopted that
compensates for possible involuntary influences on results due to the lack of a blind.
The adopted measures, not described in other paragraphs, have been the following:
 inclusion criteria limited to subjects not responding to protocol treatments. The
definition of not responding can be approximate, and therefore has been coded by
identifying: 1)high VAS levels for recruitment; 2) as high levels of successful endpoints
of the study. Combining these two criteria, it is then possible to give a clear meaning to
the definition of not responding upon entry in the study, and of responding upon
exiting the study, depending on scientific reference literature and patient’s life quality.
 In general, the scientific literature agrees in taking into account as valid measuring
instruments: Visual Analogue Scale (VAS), Verbal Rating Scale (VRS),
Numerical/Numeric Rating Scale (NRS), but there is a strong trend to prefer the VAS
scale. In terms of VAS scale, the concept of high pain is assigned to values >= 6/10. This
therefore is the minimum inclusion threshold that has been set for studies about
benign chronic pain. In oncology pain, this minimum threshold has been further raised
to 7/10. The max. enrolment threshold foreseen in all studies is a VAS 10/10, therefore
the maximum possible value.
 about oncology pain and in the RCT study, savings on drugs have been computed, a
further indirect measure of the treatment effectiveness
 The medical personnel that performed the treatments have been separated from the
ones that performed VAS measures. A further separation has been adopted for
responsible people for statistical analysis, who never came in contact with the patients.
Statistics Analytically, using as criteria of responders to pharmacological therapies
used upon recruiting, a pain reduction by at least 50% of the initial estimation (largely
shared standard), in a VAS scale from 0 to 10, the minimum inclusion value is a VAS>5.
 Success endpoints have been set, pointing out a pain reduction as output with respect
to the initial evaluation, by at least 50%, this in at least 70% of the enrolled cases.
Taking into account that these are cases not responding to other treatments, the
combined threshold of high entry VAS and high success % associated with high clinical
significance, strongly contributes to minimize the effects of involuntary interferences
in the open study.
 Theoretically, with reference also to literature used in analytically verifying the
incidence of placebo (see Section 13), data emerging from scientific literature allow
39 | P a g e
further clarifying the method effects depending on placebo and/or pharmacological
therapies used upon enrolling
 In studies have been processed only after the study was closed to avoid influences
about its performance.
Role of researchers engaged in the studies
Main investigator for clinic research:
Alessandro F. Sabato, MD, PhD. Professor in Anestesia and Reanimation, Università degli
Studi di Roma Tor Vergata. (Roma, Italy)
Antonello Gatti, MD. Clinica Responsible for Policlinico Universitario di Tor Vergata, U.O.S.D.
Pain Management Center Departement Of Intensive Care, Pain Medicine and Anesthesiology
(Roma, Italy)
Sandra Spaziani, MD. Primary doctor of Unità Operativa di Terapia Antalgica e cure
palliative of Ospedale Umberto I° di Frosinone. (Frosinone, Italy)
Vittorio Iorno, MD. Medical Responsible of the Centro di terapia del dolore “Mario Tiengo”.
IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena. (Milano, Italy)
Basic and applied research, analytic support for preparing the protocols:
Giuseppe Marineo, MD, DSc. Delta Research & Development. Centro Ricerche Bioingegneria
Medica – Università degli Studi di Roma Tor Vergata
Control type
ST5- Oncology Pain - ST5-Neuropathic Pain - St5-Historical Monitoring and Follow-up
Data:
Self-controlled vs protocol pharmacological therapies used upon recruitment. Unblinded.
ST5-RCT Trial: RCT vs Multidrug Therapy (AMITRIPTYLINE + OXYCODONE +
CLONAZEPAM). Two-armed control study. Unblinded.
Assignment method for treatment
Randomized upon presenting
40 | P a g e
Sequence and length of all study periods
ST5- Oncology Pain - ST5-Abdominal Cancer
Recruitment
upon
presentation
10 treatments for
stabilization
and
check of success
end-points
(10
days)
Ethical
treatment
maintenance upon need till
natural illness conclusion
(variable length)
Check
of
effectiveness
maintenance (Pain relief >=
stabilization).
Biostatistic
analysis. Success end-points
and safety.
ST5-Neuropathic Pain - ST5-Historical Monitoring and Follow-up Data
Recruitment
upon
presentation
10 basic treatments/week. One suspension week
every treatment week. Maximum six global
treatment weeks. Follow-up at one, two and three
months from cycle completion. Average length1.2
cycles
Biostatistic
analysis.
Check
of
success
endpoints (Pain relief >=
50%) and safety .
ST5-RCT Trial
Randomized
recruitment
upon
presentation
10 treatments in two consecutive
weeks (1 treatment every day for 5
days/week) and follow-up at one,
two and three months from cycle
completion.
Biostatistics
analysis.
Check
of
success
endpoints (Pain relief >=
50%) and safety.
ST5- Oncology Pain - ST5-Abdominal Cancer: guaranteeing a good clinical practice and
performance of studies: Comitato Etico Osp. Umberto I° Frosinone. Spontaneous study.
ST5-Neuropathic Pain (1) - ST5-Historical Monitoring and Follow-up Data: guaranteeing
a good clinical practice and performance of studies: Direzione Sanitaria PTV and Prof.
Alessandro Fabrizio Sabato - Comitato Etico Policlinico Tor Vergata. Ordinario di
Anestiosiologia e Rianimazione Università degli Studi di Roma "Tor Vergata". Responsible for
Dept. Medicina Critica e Scienze Anestesiologiche "Policlinico Tor Vergata". Spontaneous
study.
ST5-RCT Trial (1): guaranteeing a good clinical practice and performance of studies:
Direzione sanitaria IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli, Regina
Elena, Milano. Spontaneous study.
Note 1. Studies following European authorization to commercialization.
41 | P a g e
Ad interim analysis.
Pathology
FBSS
Lumbsc.
PHN
Trigeminal
Post Surg.
Brach. Plex
Pudendal
LBP
SCS
Benign pain protocols comparison
(only approximate for numeric sample diversity)
% Responders Pain relief>=
N=
50% at 1 month or more
Side or undesired effects
from cycle completion
Protocol 2
Protocol 2
Protocol 1
Protocol 1
Proto Proto
without
without
with interwith intercol 1 col 2
inter-cycle
inter-cycle
cycle pause
cycle pause
pause
pause
80.44
0%
85.25
0%
8
72.09
100
0%
0%
80.97
0%
0%
14
84.08
100
0%
0%
80.2
0%
63.13
0%
81.66
0%
4
96.15
0%
Section 10.2 - Case report forms for deaths, other serious adverse events and
withdrawals for adverse events (submit under item 12 - FDA form 356h)
No event to be reported.
42 | P a g e
Section 10.3 - Individual patient data listings for safety data. Individual patient
listings of efficacy data are not necessary.
Main table
Study title
Primary
endpoint:
Pain relief
>=50% in
at least
70% of
cases
ST5Oncology
Pain
Yes (100%
at the end
of the
stabilizatio
n cycle)
ST5Abdominal
Cancer
Yes (100%
at the end
of the
stabilizatio
n cycle)
ST5Neuropath
ic Pain
Yes
(80.09%)
Secondary
endpoint if
foreseen:
Analgesic
drugs
consumpti
on
reduction
Complete
reduction
during
cycle in
72% of
cases.
Strong
reduction
of dosing in
the
remaining
28%
Complete
reduction
during
cycle in
81.8% of
cases.
Strong
reduction
of dosing in
the
remaining
18.2%
NA
Responder
s
percentag
e
(Pain
relief
>=50%)
Confidenc
e Interval
P-value
Cycle
length
(stabilizati
on)
Follow-Up
100% at
the end of
the
stabilizatio
n cycle (10
treatments
)
95%
P<0.0001
10
Treatments
(optimized
protocol)
Till natural
illness
conclusion.
100% at
the end of
the
stabilizatio
n cycle (10
treatments
)
95%
P<0.001
10
Treatments
(optimized
protocol)
Till natural
illness
conclusion.
Average
80.09%
95%
P<0.001
10-12
Treatments
(basic
protocol
unchanged
sinvce the
beginning
of studies
in 1998)
Min. 3
months
43 | P a g e
ST5-RCT
Trial
Yes
(96.1%)
ST5Historical
Monitorin
g and
Follow-up
Data
Yes
(79.58%
including
years of the
developme
nt phase
from 1999
to 2002)
Analgesic
consumptio
n at three
months
from
the
last
treatment
with
Scrambler
Therapy
decreased
by -71.9%
compared
to an initial
-67.7%
with opiate
doses, by 71.9% in
anticonvuls
ants and by
-57.3% in
antidepress
ants.
NA
96.1% at 1
month,80.7
6% at 2
months,
73% at 3
months.
(Complete
absence of
pain at 3
months:65
%)
95%
Anova
P<0.0001,
TukeyKramer,
Multiple
Compariso
ns Test
P<0.001
10
Treatments
(optimized
protocol)
Min. 3
months
FBSS 80.4
%,
Lumbsc.85.
2 %,PHN
72
%,Trigemin
al 80.9
%,Post
Surg.84%,B
rach. Plex
80.2%,Pud
endal 63,1
%,LBP
81.66,Other
s 85.1%
95%
These data
also
include
developme
nt steps
(19982003).
Since 2004
the method
is stable
(P<0.001)
10-12
Treatments
from 2004
onwards
(stabilized
method),
Basic
protocol
unchanged
from the
beginning
of studies
in 1998
Min. 3
months
44 | P a g e
Section 11.0 - Comparative table with scientific literature (efficacy evaluation)
Study title or
references
N. pz.
Active principle
or medical device
Treated
pathologie
s
Paired T test
P<0.0001
From 9.1 to 0.7
Paired T test
P<0.001
From 8.6 to 1.5
100%
scientific
literature
Paired T test
P<0.001
From 6.56 to 2.4
80.09 %
scientific
literature
Anova
P<0.0001,
Tukey-Kramer,
Multiple
Comparisons
Test P<0.001
From 8 to follow
up:
0.7 (1 month) ,1.4
(2 months), 2 (3
onths)
Tot. average100%
Single cases:
96.1% at 1
month,80.76
% at 2
months,
73% at 3
months.
Complete
absence of
pain at 3
months:65.3
%
FBSS 80.4 %,
Lumbsc.85.2
%,PHN 72
%,Trigemina
l 80.9 %,Post
Surg.84%,Br
ach. Plex
80.2%,Pude
ndal 63,1
%,LBP
81.66,Others
85.1%
0% within
the average
shown in the
study.
scientific
literature
0% within
the average
shown in the
study.
From 5.72 to
4.49
VAS
DECREASES(010)
ST5- Oncology Pain
33
Scrambler Therapy
ST5
ST5-Abdominal Cancer
11
Scrambler Therapy
ST5
ST5-Neuropathic Pain
226
Scrambler Therapy
ST5
ST5-RCT Trial
52
Scrambler Therapy
ST5
ST5-Historical
Monitoring and
Follow-up Data
2297
Scrambler Therapy
ST5
FBSS,Lumbs
c.,PHN,Trige
minal,Post
Surg.,Brach.
Plex,pedend
a,LBP,Other
s
1
229
Gabapentin
(Concomitant
tricyclic
antidepressants
and/or narcotics
were continued )
PHN
P<.001
VAS from 6.3 to
4.2
2
57 (41
complet
ed the
trial)
35 with
diabetic
neuropathy,
22 PHN
P<0.05 for the
combination
vs. placebo
3
1145
(System
atic
Review)
5.72 at baseline,
4.15 with
gabapentin, 3.70
with morphine,
and 3.06 with the
gabapentinmorphine
combination
Mean pain relief
with opioid was
about
30% in both
neuropathic and
nociceptive pain
opioids in
chronic non-cancer
pain (fentanyl,
hydromorphone,
methadone,
morphine,
oxycodone)
Colon,gastri
co,ovarico,p
ancreas,pol
omone,pros
tata,renale,v
escica,linph
oma,bones,
mammella
cancer
patients
(pancreas,
colon,
gastric)
FBSS,Lumbs
c.,PHN,Trige
minal,Post
Surg.,Brach.
Plex,Pudend
al,LBP,Othe
rs
PSNP,PHN,S
CS
Responders
percentage
(Pain relief
>=50%)
100%
P- value
45 | P a g e
0% within
the average
shown in the
study.
Placebo
estimation
scientific
literature
scientific
literature
VAS from 6.5 to
6.0
4
Systema
tic
Review
NSAIDs, skeletal
muscle relaxants
(for acute low back
pain), and tricyclic
antidepress. (for
chronic low back
pain) are effective
for pain relief.
Mean VAS
reduction by 1-2
points
(normalized on a
0-10 scale)
Data referred to scientific literature present in the table
1: JAMA. 1998 Dec 2;280(21):1837-42.Gabapentin for the treatment of postherpetic
neuralgia: a randomized controlled trial.
2: N Engl J Med. 2005 Mar 31;352(13):1324-34.Morphine, gabapentin, or their combination
for neuropathic pain.
3: Pain. 2004 Dec;112(3):372-80.Opioids in chronic non-cancer pain: systematic review of
efficacy and safety.
4: Ann Intern Med. 2007 Oct 2;147(7):505-14. Medications for acute and chronic low back
pain: a review of the evidence for an American Pain Society/American College of Physicians
clinical practice guideline. http://www.annals.org/cgi/content/full/147/7/505
Section 12.0 - Any additional information pertinent to the evaluation of safety should
also be
included.
The clinical practice in hospitals not included in experimentations that from 2004 onwards
use the method in the normal delivery of services to the public (benign and oncology chronic
pain) is for patients not responding to other treatments; the absence of side or undesired
effects has been confirmed for any used treatment protocol. The protocol that is normally
used in the usual clinical practice of benign chronic pain is 10 treatments performed in two
consecutive weeks. The compared monitoring analyses, though on non-homogeneous cases
and different sample size, currently point out this protocol as optimum in terms of better
results in the short and medium/long term.
46 | P a g e
In current clinical practice, the patient managing scheme is as follows:
Oncology Pain
Basic cycle 10 consecutive
treatments (1 every day or
upon need where necessary)
Other treatments upon
need for the whole time
that they need
Benign chronic pain protocol 1 (alternate of 1 week with therapy/1 week with
suspension)
Basic
cycle
10-30
treatments (average 12
treatments)
No recurring pain. The
patient does not need a pain
therapy any more (typically
mono-neuropathies).
Follow – Up (1-3 months)
Recurring
pain.
The
patient needs a recall
treatment (typically polineuropathies).
Benign chronic pain protocol 2 (current standard, no inter-cycle pause)
Basic
cycle
10-12
consecutive treatMent
in two weeks
No recurring pain. The patient
does not need a pain therapy
any more (typically mononeuropathies).
Follow – Up (1-3 months)
Recurring
pain.
The
patient needs a recall
treatment (typically polineuropathies)
B. Human Pharmacokinetics, Bioavailability, and Clinical Pharmacology
Studies
Not applicable
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