Randomized, Single-blind, Multicenter, Crossover, Controlled Clinical Trial to Compare Difference on the Visual Analogue Scale With Two Modes of Spinal Cord Stimulation in Patients With Post-Laminectomy Syndrome in Testing Phase
Phase: NA
Conditions: Laminectomy, Post-laminectomy Syndrome, Spinal Cord Syndrome, Failed Back Surgery Syndrome
Sponsor: Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León

 
 
CLINICAL RESEARCH PLAN INVOLVING A MEDICAL DEVICE 
 
 
 
 
 
 
 
 
“MEDULLARY STIMULATION” 
 
 
 
TITLE: “Randomized, single-blind, multicenter, crossover, controlled 
clinical trial to compare the difference in visual analog scale in two 
modes of spinal cord stimulation in patients with postlaminectomy 
syndrome in test phase” 
 
 
CODE: EST-MED-2018-01 
 
 
 
VERSION/ DATE: 
 
Version .2.0 - 04 june 2018. 
 
 
 
PROMOTOR: Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León 
(IECSCYL)-Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
 
 
NATIONAL COORDINATOR: Dr. Francisco José Sánchez Montero 
 
 
 
 
 
CONFIDENTIAL 
This protocol and the information it contains are considered confidential/secret information of 
the Study Sponsor. Dissemination may only be made with the express written permission of the 
Sponsor. 
 
 
 

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A.1 
GENERAL 
 
TITLE 
 
“Randomized, single-blind, multicenter, crossover, controlled clinical trial to compare 
the difference in visual analog scale in two modes of spinal cord stimulation in patients 
with postlaminectomy syndrome in test phase” 
 
CODE 
 
EST-MED-2018-01 
 
 
PROMOTOR 
 
Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León 
(IECSCYL)-Instituto de Investigación Biomédica de Salamanca (IBSAL) 
Hospital Virgen de la Vega, 10ª planta 
Paseo de San Vicente, 58- 182 
37007 Salamanca 
Tlf: 923 210960/ 923 090470 ext. 55113 
 
NATIONAL COORDINATION 
 
Dr. Francisco José Sánchez Montero 
Servicio de Anestesiología, Reanimación y Tratamiento del dolor. 
Facultativo Especialista de Area 
Hospital Universitario de Salamanca 
 
PRINCIPAL INVESTIGATORS 
 
Dr. L Mario Vaquero Roncero 
Servicio de Anestesiología, Reanimación y Tratamiento del dolor. 
Facultativo Especialista de Area 
Hospital Universitario de Salamanca 
 
Dr. Jose Antonio Sáenz López 
Servicio de Anestesiología, Reanimación y Tratamiento del dolor. 
Facultativo Especialista de Area 
Hospital San Pedro de Logroño 
 
 
 
 

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COORDINATION AND MONITORING 
 
Tride Asesores  
C/Raimundo Fernández Villaverde 55, 6º Izda. 
28003 Madrid 
Tel. 91 5330264  
Persona de contacto: Piedad Martín, PhD 
 
RESEARCH MEDICAL DEVICE 
 
The neurostimulation system device Medtronic® consisting of electrodes Vectris 
SureScan MRI 1x8 Subcompact Model 977A 260/75/90 and a rechargeable 
neurostimulator compatible with magnetic resonance imaging. 
The EVOLVE programming guide is enclosed with the device, which is a 1 KHz 
frequency programming protocol adapted to the Medtronic®: SureScanTM 
neurostimulation system. 
 
Clasification 
 
Randomized, open-label, crossover, multicenter phase IV clinical trial with medical 
device.  
 
Ethics comitee  
 
CEIM Hospital Universitario de Salamanca  
CEIM Hospital San Pedro de Logroño. 
 
Main objective 
 
To compare the values of the visual analog scale (VAS) in patients with postlaminectomy 
syndrome with leg pain or leg and lumbar pain, applied at baseline and at the end of the 
test phase, using a single neurostimulator per patient, under conventional spinal cord 
stimulation (CMS) or under stimulation with the EVOLVE protocol (EME). 
 
Design 
 
Prospective clinical investigation in phase IV, randomized, comparative with control 
group, crossover and single-blind. 
 
Disease or disorder under study 
 
Postlaminectomy syndrome in patients undergoing spinal surgery. 
 
 
 
 

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INDEX 
Page 
A.1 
GENERAL ……...……………………………………………………………4 
A.1.1 Introduction 
A.1.2 Identification of the clinical research plan 
A.1.3 Promotor 
A.1.4 Principal investigator, coordinating investigator and research centers 
A.1.5 Global overview of clinical research 
A.2 
IDENTIFICATION AND DESCRIPTION OF THE PRODUCT UNDER 
INVESTIGATION …………………………………………………………………..12 
A.3 
JUSTIFICATION OF THE CLINICAL RESEARCH DESIGN………......13 
A.4 
RISKS AND BENEFITS OF THE PRODUCT IN CLINICAL RESEARCH 
………….……………………………………………………………………………....14 
A.5 
OBJECTIVES AND HYPOTHESES OF CLINICAL RESEARCH............14 
A.6 
CLINICAL RESEARCH DESIGN …………….……………………….…...15 
A.7 
STATISTICAL CONSIDERATIONS….…………………………….…..….20 
A.8 
DATA MANAGEMENT…..………………………………………….…..…..21 
A.9 
AMENDMENTS TO CRP..…………………...………………………….…..21 
A.10 DEVIATIONS FROM THE CLINICAL RESEARCH PLAN…..…….…..22 
A.11 PRODUCT ACCOUNTING……………...…………………………….…….22 
A.12 COMPLIANCE STATEMENTS…………...………………………….…….22 
A.13 INFORMED CONSENT PROCESS………………….……………….…….22 
A.14 ADVERSE EVENTS, ADVERSE EFFECTS OF THE PRODUCT AND 
PRODUCT DEFICIENCIES……….………………………………………….…….23 
A.15 VULNERABLE POPULATION...……………………………………….…..26 
A.16 SUSPENSION OR EARLY DISCONTINUATION OF CLINICAL 
TRIALS ………………………………………………………………………….……26 
A.17 PUBLICATION POLICY…………………………………………….………27 
A.18 BIBLIOGRAPHY……………………………………………………………..28 
 
ANNEX I 
ABBREVIATIONS AND DEFINITIONS  
ANNEX II 
VISUAL ANOLOGIC SCALE  
ANNEX III OSWESTRY QUESTIONNAIRE 
__________________________________________________________________ 
 
 
 

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A.1     GENERAL 
 
A.1.1 Introduction 
 
 
It is estimated that one in five Europeans (19%) suffers from chronic pain. In Spain, recent 
data estimate that the prevalence is slightly lower than the European average (17%). 1 
Chronic pain, in addition to considerably affecting the patient's work, social and family 
environment, represents a considerable economic burden for the healthcare system. 2 
According to a European survey, half of chronic pain patients feel tired all the time and 
40% feel helpless or unable to think or function normally. 3 Although the cost of chronic 
pain is difficult to calculate, as global data is not available, it is believed to cost more than 
300 billion euros in Europe4 or around 1.53% of GDP. In Spain, it is estimated that the 
total cost (direct and indirect) of chronic pain is 16,000 million euros per year, which 
represents 2.5% of GDP. Thus, in Spain, neuropathic pain alone costs 5,064 euros per 
year/per patient. 5 These figures should, in any case, be viewed with caution, since there 
are no global studies in our country to support them either. 
 
.- Lumbar pain 
Chronic low back pain represents one of the most common causes of disability, being 
very prevalent and generating enormous direct and indirect socioeconomic costs, as well 
as a great demand for consultations in primary and specialized care 6. It is also the main 
problem associated with a poor perceived quality of life in people with chronic pain. 
7. Chronic low back pain has become one of the most expensive medical conditions to 
treat, with an adult incidence of 37% and a lifetime incidence of 60-85%, which generates 
very high costs 8,9. The prevalence of low back pain in Spain is around 20%,  
10 and the general trend does not appear to be downward, with an increase in recent years 
11. 
 
.- Postlaminectomy syndrome or FBSS 
A particularly relevant pain condition is post-laminectomy syndrome, which affects some 
patients after laminectomy back surgery. It occurs when the posterior laminectomy has 
failed to relieve the patient's back pain, resulting in associated disability. The portion of 
the vertebra that connects the main body of the bone to the spinous process is the lamina. 
Well, a laminectomy is the removal of the lamina or associated bone spurs, relieving the 
accumulated pressure on the spinal nerves in various back conditions. This pain, the most 
prominent symptom of the syndrome, persists in the back and/or legs despite surgery. 
However, this term is also referred to as failed back surgery syndrome or "failed back 
surgery syndrome” (FBSS), since in spine surgery there are anterior approaches that do 
not require laminectomy. This pain, which is referred to the lumbar area or the lower back 
or leg, appears after surgery without complications (compression, infection, etc.). The 
International Association for the Study of Pain defines FBSS as lumbar spinal pain of 
unknown origin persisting despite a surgical intervention or appearing after an 
intervention to treat spinal pain located in the same topographic area 12. Although the 
terms postlaminectomy syndrome and FBSS are used interchangeably, they are not really 
synonymous. Even more recently, new terminology has been proposed, such as persistent 
postoperative syndrome (PPS).  
13 or lumbar postoperative syndrome, 14,15 not to imply that the pain is exclusively or 
necessarily due to surgical failure. The incidence of FBSS after back surgery is 10%-40% 

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16. In fact, the term FBSS encompasses several pathological conditions with common 
diagnoses such as foraminal stenosis, painful disc, pseudarthrosis, neuropathic pain, 
recurrent disc herniation, facet joint pain and sacroiliac joint pain 17. The most important 
conditions are traditional postlaminectomy syndrome (as defined above) and lumbar 
canal stenosis. 
 
Basically, two types of pain can be distinguished in postlaminectomy syndrome. One is lumbar, 
generally of somatic and mechanical characteristics, and the other is neuropathic, located in the 
lower extremities. Low back pain can also sometimes have neuropathic aspects, since the way in 
which most spinal surgery is currently performed causes important denervations of the 
paravertebral musculature of the operated area. Low back pain is therefore fundamentally 
musculoskeletal, with a pattern of irradiation that is generally not metameric, and may increase at 
night. It is mechanical, worsening with flexions, extensions and rotations of the spine. 
Neuropathic pain predominates in the lower extremities and frequently presents insidiously, with 
a metameric pattern of irradiation. Patients with neuropathic pain usually report allodynic 
sensations (non-nociceptive stimulus) in the extremity, and a decrease in temperature in the 
extremity, both subjectively and objectively, is frequently observed. In these neuropathic 
conditions there are paroxysms of pain and, on occasions, trophic and vasomotor changes may 
appear in the affected extremity 18. 
 
The clinical history and the general characteristics of the pain will therefore define 
whether we are dealing with somatic pain due to excess nociception, neuropathic pain 
with a predominantly distal predominance, or if the picture is mixed. We can also evaluate 
the possible influence of the sympathetic nervous system in these pain syndromes 
according to the degree of vasomotor and thermoregulatory alterations in the lower 
extremities. 
 
Post-laminectomy syndrome is not a diagnosis and the cause is unknown. One of the 
primary theories blames scar tissue developed in the epidural space of the spine after 
surgery as the cause of the pain, as it generates epidural fibrosis. Some of the other 
possible causes of post-laminectomy syndrome include: recurrence of disc herniation, 
disc degeneration, incomplete removal of the lamina, adhesive arachnoiditis, residual 
lateral foraminal restenosis, and problems beyond the strictly surgical (psychosocial and 
occupational) 19. 
 
.- Treatment of postlaminectomy syndrome or FBSS 
Although post-laminectomy syndrome can be long-lasting and can significantly 
interfere with an individual's lifestyle, proper treatment can provide great pain relief and 
improve the quality of life for these patients. Treatment options for postlaminectomy 
syndrome or FBSS include many alternatives ranging from pharmacological, surgical, 
different techniques and mixed. The most standardized treatment is epidural injection 
(block) of steroids, local anesthetics or other drugs (opioids, clonidine and orgoetine).  
20 With these treatments, pain relief results can be achieved for up to 24 months. 
 21,22  Pharmacological treatments have been widely used but little studied. Opioids are 
usually associated with many adverse effects. Gabapentin produces an improvement 
over naproxen 23 or added to epidural steroid injections. 24 Spinal re-intervention has 
yielded very mixed results, ranging from 30% to 80% success 25-27 , but with a poor 
degree of evidence and rather short term. Root blocks allow us to correctly define 
whether or not the pain is dependent on one or more roots. Neuroablative techniques are 
also used. Epidural adhesiolysis has shown some short-term benefit over epidural 
injections 28-30 . Another option that is considered particularly in those patients in whom 

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medical treatment has failed and re-intervention is not advisable, is spinal cord 
stimulation, 31,32 on which the technique described in this protocol is based.  
 
 
.- Medullary Stimulation 
 
Melzack and Wall (1965) 33 proposed a completely new neurophysiological theory to try 
to explain how the central nervous system could act at the level of sensory afferents to 
produce different painful phenomena, the "gateway theory". According to this theory, the 
myelinated, large-caliber fibers inhibit, and the fine-caliber fibers, A-d and C, facilitate, 
respectively, the transmission of all nociceptive afferent information at the level of the 
spinal cord, specifically in the posterior horn. The myelin fibers would activate the T 
cells, but previously they would also activate the Rolando gelatinous substance, which in 
turn would exert a presynaptic inhibitory action on the T cells. On the other hand, the 
amyelinic fibers would facilitate the pain transmission cells (T cells), but previously 
inhibiting the gelatinous substance, thus losing its inhibitory function on transmission. 
Thus, this medullary control would normally act through myelin fibers inhibiting the 
passage of low threshold sensations, preventing them from being interpreted as painful. 
When the stimulus threshold is more intense, conducted by the myelin fibers, the impulses 
inhibit the gelatinous substance, so that the impulse has free passage to higher centers and 
these can still block the passage of the nociceptive sensation at the medullary level.  
 
Spinal cord stimulation (also called spinal neurostimulation or spinal electrical 
stimulation) produces analgesia through electrical stimulation by means of electrodes 
placed in the epidural space of the spinal column at the dorsal level. In traditional 
stimulation, paresthesias are provoked. These paresthesias should cover at least the 
painful area. Spinal cord stimulation is effective in reducing neuropathic pain, improving 
function and improving quality of life in patients with FBSS. This technique shows its 
efficacy when other techniques fail 34. 
 
Stimulation has also been compared to conventional medical treatment, showing 
improvement in low back and leg pain relief, quality of life, functional capacity and 
treatment satisfaction 35,36. Stimulation is also cost-effective, 37,38 especially when long-
term results (9 years) are assessed 38. This stimulation technique is often underutilized 
despite the fact that it presents fewer complications and lower costs than re-intervention.  
39. Thus, complications are slightly more than twice as high with surgical re-intervention 
as with spinal cord stimulation 40. 
 
.- Spinal cord stimulation technique 
 
The components that make up the spinal cord stimulation equipment are: 
- a neurostimulator (external or implantable)  
- electrodes (which transmit the electrical charge) 
- electrode extensions (allowing the electrode to be connected to the external 
neurostimulator)   
- an external patient programmer to control the system. 
- a charging system, if the neurostimulator is rechargeable.  
 
 

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The neurostimulator is the power source (battery) of the neurostimulation system. It 
contains electronic components that generate the electrical impulses. Once the electrodes 
are in place, a test stimulation is performed to confirm the correct position of the 
electrodes. During test stimulation, an external neurostimulator is used to determine 
whether an implantable neurostimulator is the appropriate choice for the patient. 
The electrodes consist of thin wires with an insulating coating that are responsible for 
transmitting the electrical impulses to the area where pain signals are to be blocked.  
In the test phase the electrodes require an extender to be connected to the external 
neurostimulator. 
The patient programmer is a handheld device used to select and adjust the stimulation. It 
also has a detachable antenna in case it does not easily reach the neurostimulator 
implantation site.  
In some cases an implanted charging system is used to charge the rechargeable 
neurostimulator battery (rechargeable neurostimulator). 
 
Implantation of a spinal neurostimulation system is performed by placing the electrode 
(or electrodes) in the spinal epidural space, usually percutaneously. The procedure is 
performed in the operating room under local anesthesia or controlled sedation, so that the 
patient can cooperate and describe the paresthesia induced in the analgesic area. The 
placement and progression of the electrode(s) is performed under fluoroscopy. The 
implantation is performed in two phases: in the first phase the electrode(s) is connected 
to the external generator to test the result (test phase); in the second phase the definitive 
generator is implanted if the first phase has been successful.  
 
In the first phase the epidural space is located and then the electrode(s) is inserted under 
fluoroscopic guidance, through the needle, until it is positioned at the dorsal level (T9-
T10). Depending on the technique, number of electrodes, and experience, a surgical 
incision will be made prior to needle insertion. The optimal position of the electrode(s) 
will be reflected by the correct coverage of the pain area by paresthesias. Subsequently, 
the electrode is connected to the programmer, setting an amplitude, pulse duration and 
frequency determined objectively by obtaining an adequate level of paresthesias. Once 
the correct placement of the electrode(s) has been checked, it is fixed and tunneled, so 
that it faces outwards. The electrode(s) are then connected to the temporary percutaneous 
extension and, finally, loosely placed in the form of a loop, they are "buried" in the 
incision, so that they are protected. In phase 2, after a trial period (several days) if the 
improvement of pain is considered adequate by both the patient and the therapeutic team, 
the spinal cord stimulation system is permanently implanted. The generator is implanted 
under sedation and analgesia (the patient's collaboration is no longer necessary) in the 
chosen area in a subcutaneous pocket created at a depth of 1 cm from the skin surface. 
The connection of the electrode(s) to the generator is made by means of a tunneler. 
 
.- Neurostimulation parameters 
 
The parameters that need to be adjusted in spinal neurostimulation are three: frequency, 
amplitude and pulse width. Frequency determines the quality of paresthesia, the most 
commonly used being around 60 Hz; pulse width affects the area of paresthesia, and 
amplitude affects the intensity of the stimulus 41. If at the end of the test phase (at the 
end of phase 1 discussed above) pain relief is reduced by 50% or more, the result of the 
procedure is considered positive 42. 
 

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JUSTIFICATION 
A recent Cochrane Library review concludes that conventional spinal cord stimulation 
for FBSS pain relief requires more clinical studies and better designs to demonstrate its 
superiority over other therapeutic options 43. Therefore, although spinal cord stimulation 
is accepted by the FDA (Food and Drug Administration) and the EMA (European 
Medical Agengy), new techniques are being introduced that offer better results in terms 
of pain relief 36,44. Among these techniques is the high-dose modality, which avoids the 
annoying sensation of paresthesia that substitutes pain with the conventional technique. 
In order to provide greater rigor and scientific quality, the present study compares, using 
the same neurostimulator per patient, two different modes of spinal cord stimulation:  
 
1. Conventional spinal cord stimulation (CS) (control or CS) with paresthesia and a 
standard frequency (60 Hz).  
2. High-dose spinal cord stimulation (1000 Hz) or EVOLVE (EME) protocol 
(experimental arm or EME). 
This comparison is carried out by means of a design with a high degree of scientific 
evidence, randomizing the global sample of patients to each of the two stimulation 
branches of the study (blinded for the patient) and crossing the branches after a washout 
period.  
 
 
A.1.2 Identification of the clinical research plan 
 
a) Title of clinical investigation 
. 
“Randomized, single-blind, multicenter, crossover, controlled clinical trial to compare 
the difference in visual analog scale in two modes of spinal cord stimulation in patients 
with postlaminectomy syndrome in test phase” 
 
b) Reference number identifying the specific clinical investigation 
Protocolo reference: EST-MED-2018-01 
 
c) Version: 2.0 date 04 june 2018 
 
d) Summary of revision history in case of amendments 
Not applicable. 
 
e) Version/issue number and reference number, if any, with page number 
Not applicable. 
 
A.1.3 Promotor 
Name and address of the sponsor of the clinical investigation: 
 
Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León 
(IECSCYL)-Instituto de Investigación Biomédica de Salamanca (IBSAL) 
Hospital Virgen de la Vega, 10ª planta 
Paseo de San Vicente, 58- 182 
37007 Salamanca 
Tlf: 923 210960/ 923 090470 ext. 55113 

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A.1.4 Coordinating Researcher, Principal Investigator, Co-Investigators and 
Research Centers 
 
a) Name and address of the Coordinator and participating researchers: 
 
 
NATIONAL COORDINATION 
 
Dr. Francisco José Sánchez Montero 
Servicio de Anestesiología,  Reanimación y Tratamiento del dolor 
Facultativo Especialista de Area 
Hospital Universitario de Salamanca 
 
HOSPITAL UNIVERSITARIO DE SALAMANCA  
Principal Investigator 
 
Dr. L Mario Vaquero Roncero 
Servicio de Anestesiología Reanimación y Tratamiento del dolor. 
Facultativo Especialista de Area 
 
Co- Investigators 
 
Dr. Felipe Hernández Zaballos 
Servicio de Anestesiología Reanimación y Tratamiento del dolor. 
Facultativo Especialista de Area 
 
Dr. Juan Ignacio Santos Lamas 
Servicio de Anestesiología Reanimación y Tratamiento del dolor. 
Facultativo Especialista de Area 
 
Dra. Laura Alonso Guardo 
Servicio de Anestesiología Reanimación y Tratamiento del dolor. 
Facultativo Especialista de Area 
 
Dr. David Sánchez Poveda 
Servicio de Anestesiología Reanimación y Tratamiento del dolor. 
Facultativo Especialista de Area 
 
Dr. José Carlos Garzón Sánchez  
Servicio de Anestesiología Reanimación y Tratamiento del dolor. 
Facultativo Especialista de Area 
 
Dr. José María Calvo Vecino 
Servicio de Anestesiología Reanimación y Tratamiento del dolor. 
Facultativo Especialista de Area 
 
 
 
 

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HOSPITAL SAN PEDRO DE LOGROÑO 
Principal Investigator 
 
Dr. Jose Antonio Sáenz López 
Servicio de Anestesiología y Reanimación y Tratamiento del dolor . 
Facultativo Especialista de Area 
 
Co- Investigators 
 
Dr. Andrés García Londoño 
Servicio de Anestesiología y Reanimación y Tratamiento del dolor . 
Facultativo Especialista de Area 
 
Dr. Lourdes Ferreira Laso 
Servicio de Anestesiología y Reanimación y Tratamiento del dolor . 
Facultativo Especialista de Area 
 
Dra. Vladimir Marenco Arellano 
Servicio de Anestesiología y Reanimación y Tratamiento del dolor . 
Facultativo Especialista de Area 
 
 
b) Name and address of research centers: 
 
 
1.- Hospital Universitario de Salamanca  
Servicio de Anestesiología, Reanimación y Tratamiento del dolor. 
Paseo de San Vicente, 58- 182 
37007 Salamanca 
Tlf. 923 291100 
 
2.- Hospital San Pedro de Logroño 
Servicio de Anestesiología, Reanimación y Tratamiento del dolor. 
Calle Piqueras, 98 
26006 Logroño, La Rioja 
Tlf. 941 298000 
 
 
The sponsor should maintain an updated list of principal investigators, research centers 
and institutions. This list may be kept separate from the CIP. The final list should be 
provided with the final clinical investigation report. 
 
A.1.5 Global overview of clinical research 
 
 
Design 
Prospective phase IV, randomized, crossover, single-blind, prospective clinical 
investigation. 
 
 

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Inclusion and exclusion criteria 
 
The present study is aimed at a population of patients with postlaminectomy syndrome 
after back surgery. The inclusion and exclusion criteria are described below. 
 
Inclusion criteria 
 
1. Patients over 18 years of age. 
2. Patients with FBSS syndrome with leg pain or leg and back pain. 
3. Obtain a VAS score ≥ 7. 
4. Having received pharmacological medical treatment for at least 6 months after back 
surgery.  
5. The patient has signed the informed consent form. 
 
Exclusion criteria 
 
 
1. Patients under 18 years of age.  
2. Patients requiring any diathermic energy source (microwaves, ultrasound or short 
wave).  
3. Patients with a pacemaker. 
4. Patients with a defibrillator. 
5. Patients with a cochlear implant. 
6. Patients with other active implanted devices.  
7. Patients who are scheduled to undergo any of the following procedures during the 
duration of the study: magnetic resonance imaging, defibrillation or cardioversion, 
electrocautery, lithotripsy, radiofrequency or microwave ablation and any other high-
frequency ultrasound procedure,  
8. Women of childbearing age who are not using an adequate contraceptive method. 
9. Pregnant or lactating women. 
10. Participation in another trial. 
11. Patients who have expressed their desire not to participate in the study and have not 
formed the informed consent form. 
12. Patients with a previous failed spinal cord stimulation implant. 
 
 
 
Number of participants 
 
Twenty-four subjects will be selected who meet the inclusion criteria and do not meet 
any exclusion criteria, calculating a loss rate of 15%-20%36. 19-20 patients are 
expected to be included in the study.  
 
 
Duration of clinical research 
 
 
A total duration of 18 months plus an additional 6 months to submit the final report is 
foreseen, with the following schedule for the study: 
 

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12 
 
 
 
 
Start of the study: planned for July 2018 To be determined based on deadlines.  
Inclusion period: 16 months, until November 2019. 
Follow-up period: planned until January 2020. 
Analysis and report: expected in July 2020. 
 
 
Valuation criteria 
 
The primary endpoint is the variation in VAS between the end of EMC mode and EME 
mode.  
 
 
STUDY OUTLINE 
 
 
Evaluation 
 
Visit 1  
Basal  
Visit 2 
 
 
Visit 3 
End of 
washing 
Visit 4   
EMC 
 or EME 
VIisit 5. 
End of 
washing 
Visit 6 
EMC or 
EME 
Visita 7 
DAY of the study 
-3 * 
-2 
0 
5 
7 
12 
40±2 
Selection Criteria Evaluation 
X 
 
 
 
 
 
 
Explanation of study and signature of consent 
X 
 
 
 
 
 
 
Clinical data collection 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
VAS 
X 
 
 
X 
 
X 
X 
Oswestry Questionnaire 
X 
 
 
X 
 
X 
x 
Temporary electrode implant without stimulus 
 
X 
 
 
 
 
 
Start of spinal cord stimulation according to 
randomization A or B (day 3) 
 
 
X 
 
X 
 
 
System tolerability 
 
X 
X 
X 
X 
X 
 
Adverse effects 
 
X 
X 
X 
X 
X 
x 
Subsequent follow-up 
 
 
 
 
 
 
x 
(*) window of -2 days with respect to Visit 3. 
 
 
 
A.2 
IDENTIFICATION AND DESCRIPTION OF THE PRODUCT UNDER 
INVESTIGATION 
 
A Medtronic® neurostimulator that has implanted components that deliver electrical 
impulses to the area where pain signals are to be blocked, rechargeable and MRI 
compatible. The patient programmer is designed to program different rechargeable and 
non-rechargeable neurostimulators.  
 
The neurostimulator is the power source (battery) of the neurostimulation system. It 
contains electronic components that generate the electrical impulses. During test 
stimulation, an external neurostimulator is used to determine if an implantable 
neurostimulator is the appropriate choice for the patient. The electrode is a set of thin 
wires with an insulating coating. An electrode has small metal poles near the tip. The 
poles transmit electrical impulses to the area where pain signals are to be blocked. Two 
are usually used. The extension is a set of thin wires with an insulating coating that 
connects the neurostimulator to an electrode. Not all neurostimulation systems include an 
extension. The patient programmer is a handheld device that the patient uses to select and 

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adjust the stimulation. In the present study, spinal cord stimulation using the EVOLVE 
programming flow and conventional stimulation at 60Hz will be used. 
 
Storage conditions: The external neurostimulator is stored at room temperature. Extreme 
high or low temperatures and direct sunlight should be avoided. The device and system 
components are not water resistant. Moisture should not be allowed to enter the device or 
system components. 
 
Indications for Use: Neurostimulation is indicated in failed back surgery and complex 
regional pain syndrome. Other more exceptional indications when other therapeutic 
options fail include refractory angina pectoris, coccygodynia, interstitial cystitis, perineal 
pain, peripheral vascular pain, radiculopathies and peripheral neuropathy. 
 
Contraindications: 
Neurostimulation is contraindicated in shortwave diathermy, 
microwave diathermy and ultrasound diathermy. Diathermy energy can transfer through 
the implanted system and can damage tissues, causing serious injury or death. 
 
Description of the indications for use: The instructions for use of the device are described 
in detail in Annex 2. 
 
Programming of the implantable pulse generator 
 
In the present study, paresthesia mapping will be used for both methods. For the high-
dose experimental method (EME branch), the emitted frequency will be a 1 KHz, and the 
pulse amplitude will be increased until the patient perceives paresthesias in the 
appropriate coverage area. Depending on the participant's response to the paresthesia 
location, the anode and cathode settings will be changed to provide appropriate 
dermatome coverage. Once adequate anatomical coverage is confirmed, the pulse 
amplitude is decreased until the paresthesias disappear, and no new paresthesias manifest 
with spinal extension or flexion. For the conventional method (EMC branch), patients are 
allowed to optimize their stimulation finely over the coverage area. Each participant is 
given three program alternatives with small changes to adjust to the coverage areas during 
the study.  
 
 
A.3 
JUSTIFICATION OF THE CLINICAL RESEARCH DESIGN 
 
Traditionally, pain relief by spinal cord stimulation is related to the appearance of 
paresthesias in the affected area. Several parameters are adjusted to maximize the area 
of overexposure, such as the frequency, 45-47 and pulse amplitude 48,49. Although this 
technique has been successful in improving pain in many patients, paresthesias 
themselves can be bothersome. The occurrence of paresthesias has traditionally been 
considered a predictor of success in eliminating pain, 50 while the non-appearance of 
paresthesia would indicate failure. So far, few studies have reported pain relief below 
the threshold of paresthesia onset. Some clinical trials for pathologies other than the one 
considered in the present study have achieved relief below the threshold by reducing the 
amplitude of the stimulus 51,52. Recently, however, it has been observed in a pilot study 
that, by increasing the frequency of spinal cord stimulation to 1 KHz, it is possible to 
significantly improve pain relief compared to conventional stimulation at a lower 
frequency based on the appearance of paresthesia 44. 

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A.4 
RISKS AND BENEFITS OF THE PRODUCT IN CLINICAL RESEARCH 
 
 
a) Expected clinical benefits 
 
The benefits of spinal cord stimulation are well known and have been described in the 
introduction. The main benefit of spinal cord stimulation using the EVOLVE 
programming flow with a frequency of 1 KHz is to relieve leg pain (with or without low 
back pain) to a greater extent than the conventional system and without producing 
paresthesia.   
 
b) Expected adverse effects of the product  
Complications are independent of the stimulus used and are those inherent to the 
technique for implantation of the system according to standard clinical practice. These 
could be related to the electrode, the extension or the neurostimulator, which could move 
inside the body or erode the skin. Undesirable changes in stimulation could occur, 
possibly related to cellular changes around the poles, changes in pole position, loose 
electrical connections, or breakage of the electrode or extension. It is also possible that 
implanted materials could cause an allergic or immune response. 
 
The neurostimulation system may unexpectedly stop working due to battery depletion or 
other causes. These situations, which may include electrical shorts or open circuits and 
conductor (wire) and insulation breakage, are unpredictable. 
 
Other possible complications, more related to the technique, are infection, electrode 
migration, rejection and post-puncture headache.  
 
All these possible complications are independent of the stimulus used and are specific to 
the technique for implantation of the system according to standard practice. 
 
 
 
A.5 
CLINICAL RESEARCH OBJECTIVES AND HYPOTHESES 
 
This Clinical Research Plan has the following objectives: 
 
a) primary and secondary objectives 
 
Main objective: 
 
- To compare the values of the visual analog scale (VAS) in patients with 
postlaminectomy syndrome with leg pain or leg and lumbar pain, applied at baseline and 
at the end of the test phase, with a single neurostimulator per patient, under conventional 
spinal cord stimulation (CMS) or under stimulation with the EVOLVE protocol (EME). 
 
Secondary objectives: 
 
1. 
To estimate the proportion of patients with a minimum 50% decrease in VAS 
score at 5 days relative to baseline in each type of spinal cord stimulation (EMC or EME). 

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2. 
To evaluate the disability associated with pain at the beginning of the study and 
its possible modifications during follow-up in each type of spinal cord stimulation. 
3. 
To study the safety of the stimulation procedures under study in each type of spinal 
cord stimulation. 
 
 
b) Hypothesis  
 
The primary endpoint is the difference in VAS score applied after CME and after SCS 
compared to the VAS score applied at baseline assessment before spinal cord stimulation. 
It is assumed that SCS will achieve a 2.4 point reduction in VAS compared to CME, 
according to previous information 44. 
 
 
c) Intended applications and performance of the product under investigation 
 
The Medtronic® spinal neurostimulation system with EVOLVE flow programming is 
indicated for the pain treatment of failed back surgery syndrome and has all the elements 
for its application.  
 
d) Risks and expected adverse effects of the product  
See section A4 
 
 
A.6 
CLINICAL RESEARCH DESIGN 
 
 
A.6.1 General 
 
This is a prospective study, randomized to two modes of spinal cord stimulation control 
(CS) and experimental (EME), single-blind and crossover.  
 
Patients will be included in the study by randomizing the spinal cord stimulation mode 
after signing the informed consent form and verifying that they meet all the inclusion 
criteria and none of the exclusion criteria. Randomization will be performed by telephone 
call to the central randomization center, which will assign the patient stimulation mode 
according to the randomized list. 
 
The devices are delivered to the investigators duly manufactured and labeled and are 
deposited in the centers where they will comply with the appropriate maintenance and 
conservation conditions. The centers chosen to carry out the study have sufficient means 
and proven experience in the handling and maintenance of the devices. 
 
 
A.6.2 Product under research and testing 
 
In this study, the conventional spinal cord stimulation method (EMC limb) and the 
experimental 1 KHz spinal cord stimulation method with the EVOLVE programming 
guide (EME limb) will be used in the same patient after a washout period, randomizing 
the patient to start with one limb or the other. Randomization will be performed 

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telephonically by contact between the principal investigator and the central randomization 
center located at the CRO. It is planned to act in accordance with clinical practice in these 
patients, providing at all times what is necessary for the perfect treatment of the patients 
according to the knowledge and training of the professionals involved in the clinical 
research. 
 
 
A.6.3 Participants 
 
 
The criteria for the selection of the participant subjects are as follows. 
 
.- Inclusion Criteria 
Patients over 18 years of age. 
2. Patients with FBSS syndrome with leg pain or leg and back pain. 
3. Obtain a VAS score ≥ 7. 
4. Having received pharmacological medical treatment for at least 6 months after back 
surgery.  
5. The patient has signed the informed consent form. 
 
 
Exclusion criteria 
 
1 Patients under 18 years of age.  
2 Patients requiring any source of diathermic energy (microwave, ultrasound or short 
wave).  
3. Patients with a pacemaker. 
4. Patients with a defibrillator. 
5. Patients with a cochlear implant. 
6. Patients with other active implanted devices.  
7. Patients who are scheduled during the duration of the study for any of the following 
procedures: magnetic resonance imaging, defibrillation or cardioversion, electrocautery, 
lithotripsy, radiofrequency or microwave ablation, and any other high frequency 
ultrasound procedure,  
8. Women of childbearing age who are not using an adequate contraceptive method. 
9. Pregnant or lactating women. 
10. Participation in another trial. 
11. Patients who have expressed their desire not to participate in the study and have not 
formed the informed consent form. 
12. Patients with a previous failed spinal cord stimulation implant. 
 
 
Withdrawal criteria 
 
Patients will be withdrawn from the study if after mapping of paresthesia the electrode is 
not placed in T9/T10. 
 
Those patients who do not achieve paresthesia in the painful area in both modes will be 
withdrawn from the study. 
 

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The study will be withdrawn if the Safety and Monitoring Committee considers that the 
adverse effects are unacceptable. 
 
In the event that the patient suffers an event that prevents continuation in the study 
(serious adverse effect or similar), he/she will be treated according to the appropriate 
clinical practice at that time and his/her study termination data will be recorded. The 
patient can withdraw voluntarily without changing the relationship with his physician or 
the care he expects from him. 
 
 
Study and follow-up period 
 
Regarding the moment of inclusion, it will be one day before the placement of the 
electrode(s) and three days before the beginning of the spinal cord stimulation, once it 
has been verified that they meet all the inclusion criteria and none of the exclusion criteria. 
The patients will be included in the study in a randomized manner, after they sign their 
voluntary participation in the study before any type of intervention is performed, for 
which they will be duly informed through the patient information sheet and the oral 
explanation provided by the researcher or authorized collaborator. Randomization will be 
carried out by telephone through contact between the principal investigator and the central 
randomization center of the CRO. 
 
The expected duration of the clinical investigation is 16 months of recruitment in each 
center, plus 15 days of study and 1 month of patient follow-up, and will be maintained 
until the number of patients foreseen in the sample size described is reached. 
 
 
The duration of each patient in the study will be 15 days from the day on which the study 
scales (VAS and quality of life) are performed at the baseline visit, plus 1 month of 
subsequent follow-up.  
 
Twenty-four patients will be selected who meet the inclusion criteria and do not meet any 
exclusion criteria, calculating a loss rate of 15%-20%, it is expected that 19-20 patients 
will be included in the study. 
 
The inclusion period has been estimated at 16 months for each center. 
 
 
A.6.4 Procedures 
 
The participants who take part in the clinical research follow the following procedures 
throughout the study. They are selected at the medical visit and once it has been verified 
that they meet all the inclusion criteria and none of the exclusion criteria and their possible 
participation in the study has been decided, their participation in the study is proposed to 
them by explaining the patient information sheet and signing the informed consent form. 
From that moment on, at visit 1 (which can be the same visit or a previous one, provided 
that no procedure related to the study is performed until the consent form is signed), the 
mode of spinal cord stimulation to be applied to the patient is randomized, with a single 
device for each patient, and the study procedures will be performed. Randomization will 
be performed by telephone contact to the central randomization center of the CRO. 

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The procedures used in this work to evaluate the efficacy of spinal cord stimulation are 
the visual analog scale (VAS) and the Oswestry (OC) questionnaire on disability 
associated with low back pain (Oswestry Disability Index). The VAS makes it possible 
to measure pain intensity with maximum reproducibility between observers. It consists 
of a horizontal line of 10 centimeters, at the ends of which are the extreme expressions of 
pain perception. On the left side is located the absence or lower intensity and on the right 
side the higher intensity. The patient is asked to mark on the line the point indicating the 
intensity (see appendix 3) 53. The Owestry scale is the most recommended scale for 
measuring disability due to low back pain. 54 It consists of a self-administered 
questionnaire that measures limitations in daily activities. It consists of 10 questions with 
6 possible answers each. The score for each answer ranges from 0 (less disability) to 5 
(more disability). The result is expressed in % by dividing the total score by 50, with 0% 
being the least disability possible, and 100% the most disability. It is classified into 5 
categories: minimal disability (0% to 20%), moderate disability (21% to 40%), severe 
disability (41% to 60%), paralyzed (61% to 80%) and category requiring more careful 
evaluation (81% to 100%, could be bedridden patients or those who exaggerate 
symptoms). (See Annex 4). 
 
 Study variables 
The study is structured in 7 visits. The variables collected and structures of the visits are 
as follows: 
 
.- Visit 1 (day -3 to -5) 
The patient signs the informed consent for the study, once he/she has been informed of 
the nature of the study (the information may have been received at a previous visit). The 
selection criteria are reviewed (all the inclusion criteria must be met and none of the 
exclusion criteria must be met). Demographic data (age, sex), anthropometric data 
(weight, height), pathological history, history of vertebral and/or dorsolumbar pathology, 
history of spinal surgery, previous pharmacological medical treatment and nature of pain 
are collected. The VAS and the OC scale (disability associated with low back pain) are 
performed.  
 
.- Visit 2 (day -2) 
The electrode(s) is (are) placed. A single neurostimulator per patient (device). The patient 
is then randomized to one of the two modes of spinal cord stimulation EMC or EME, by 
telephone call, and an appointment is made for visit 3. Adverse effects and tolerability of 
the system (rejection, infection or migration) are assessed. A first 2-day washout period 
is initiated.  
 
 
.- Visit 3 (day 0) 
The first period of spinal cord stimulation begins with the branch to which the patient has 
been randomized: EMC or EME. If the patient has been assigned to the EMC control 
group, after mapping the search for the pain area, the neurostimulator is programmed to 
conventional stimulation with paresthesia at 60 Hz and a pulse width between 300-450 
μs. If the patient has been randomized to the EMC experimental group, after mapping the 
search for the pain zone, stimulation is programmed at 90% of the subthreshold with a 
pulse width of 90 μs and frequency of 1000 Hz, placing the bipole in the T9-T10 space. 
The patient is asked if there have been any complications since electrode insertion (s). 

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.- Visit 4 (day 5) 
VAS and OC scale are performed. The device is examined and questioned for possible 
adverse effects and tolerability of the system (rejection, infection or migration). The 
device is then deprogrammed and a second 2-day washout period is initiated. 
 
.- Visit 5 (day 7) 
Possible adverse effects and tolerability of the system (rejection, infection or migration) 
are questioned. The programming of spinal cord stimulation is started again, so that the 
patient is administered the MCE if he/she had received the MES, and vice versa. 
 
.- Visit 6 (day 12) 
The VAS and OC scale are performed. The device is re-examined and possible adverse 
effects and tolerability of the system are questioned. A final decision is made to implant 
or remove the device. 
 
.- Visit 7 (4 weeks after final implantation/withdrawal of system) 
The VAS and OC scale are performed. The device is re-examined and questioned for 
possible adverse effects and tolerability of the system.  
 
 
 
A.6.5 Monitoring plan 
 
 
The study will be monitored by personnel specifically contracted from a company 
external to the promoter, and an in-person visit will be made at the start, an intermediate 
visit, and a final visit at each participating center. At the beginning of the study, the first 
visit will be made, during which all aspects of the study will be explained to the research 
staff, the informed consent procedure will be explained, the protocol will be reviewed, 
the way in which patient data will be collected, the responsibilities of the researcher, the 
dispensing and maintenance of the samples and all related issues. Telephone follow-up 
will be provided to the centers throughout the duration of the study. 
 
The monitor will have access to both paper and computerized medical records and will 
ensure that patient data are properly collected and stored in the investigator's file for the 
time required by current regulations. 
 
The monitor will be informed of adverse events occurring during the clinical investigation 
through the investigator at each center and will report serious and related events to the 
authorities within the established time limits. 
 
Evaluation 
 
Visit 1  
Basal  
Visit 2 
 
 
Visit 3 
End of 
washing 
Visit 4   
EMC 
 or EME 
VIisit 5. 
End of 
washing 
Visit 6 
EMC or 
EME 
Visita 7 
DAY of the study 
-3 * 
-2 
0 
5 
7 
12 
40±2 
Selection Criteria Evaluation 
X 
 
 
 
 
 
 
Explanation of study and signature of consent 
X 
 
 
 
 
 
 
Clinical data collection 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
VAS 
X 
 
 
X 
 
X 
X 

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Oswestry Questionnaire 
X 
 
 
X 
 
X 
x 
Temporary electrode implant without stimulus 
 
X 
 
 
 
 
 
Start of spinal cord stimulation according to 
randomization A or B (day 3) 
 
 
X 
 
X 
 
 
System tolerability 
 
X 
X 
X 
X 
X 
 
Adverse effects 
 
X 
X 
X 
X 
X 
x 
Subsequent follow-up 
 
 
 
 
 
 
x 
 
(*) window of -2 days with respect to Visit 3. 
 
 
 
A.7 
STATISTICAL CONSIDERATIONS 
 
 
This is a multicenter, controlled, randomized (spinal cord stimulation method: EMC or 
EME), crossover and single-blind study. 
 
First, a descriptive analysis of the study variables will be performed, calculating the 
absolute and percentage frequency (n and %) of each category in the qualitative variables; 
in the quantitative variables, we will first study whether they fit the Gaussian distribution 
by applying the Kolmogorv-Smirnov goodness-of-fit test to the "Normal" distribution, 
showing the means and standard deviations if yes, and the medians and 25th and 75th 
percentiles if no, and if no, the medians and 25th and 75th percentiles. 
 
 
In order to respond to the main objective of the study, two variables will be calculated for 
each patient that reflect the difference between the initial VAS minus the final VAS, one 
for each type of stimulation (EMC or EME). We will calculate whether these differences 
conform to the Gaussian distribution. If they fit the "Normal" distribution, the means with 
their standard deviations will be calculated for each of them, with the Student's t-test for 
paired samples to study if this difference is statistically significant, these means will be 
adjusted for age and sex, establishing the possible statistical differences with a general 
linear model of repeated measures. In the case of not obtaining distributions that fit the 
"Normal", the medians and the 25th and 75th percentiles will be calculated, obtaining the 
possible statistical differences by applying the Wilcoxon test. 
 
For the objective of estimating the proportion of patients with a minimum decrease of 
50%, it will be calculated in each case which patients meet this condition, calculating the 
percentage of patients in each type of stimulation, and studying the possible statistically 
significant differences with the Mc Nemar test. 
 
The disability associated with pain will be evaluated with the descriptive statistics already 
mentioned and for each moment of the study and in each type of stimulation. 
 
Variables will be created with the differences between the initial and final quality of life 
scores, studying their differences with the same parameters and tests discussed for the 
differences in VAS. 
 

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The absolute and relative frequencies (%) of each of the adverse effects found in the 
follow-up will be calculated as a safety study, in the total of the study and for each type 
of stimulus. Possible differences will be studied with the Mc. Nemar test. 
 
A statistical significance level of p<0.05 is considered, thus establishing a safety level of 
95%. 
 
All analyses will be performed with SPSS software version 24.0 (IBM Corp. Released 
2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp.) 
 
Sample size 
 
The main objective of the study is to establish a mean difference in the decrease in VAS. 
Based on this, we estimate a difference between the two methods of spinal cord 
stimulation (EMC and EME) of 1.9 points, in agreement with previous data in the medical 
literature, 55 with standard deviation of 3.2 and 2.0, assuming a Spearman correlation 
between both values of 0.5 (minimum). Using the formula for paired mean difference, for 
a confidence level of 95% and a statistical power of 80%, 19 patients who meet the 
inclusion criteria and do not meet any exclusion criteria are required, calculating a loss 
rate of 20%, 24 patients are expected to be included in the study.  
 
A.8 
DATA MANAGEMENT 
 
A clinical research data collection form (CRF) will be created, where each investigator 
will collect the data of each patient participating in the study. 
 
In agreement with the scientific committee, minimum and maximum values will be 
established for each variable of the CRF, creating validation rules and messages to the 
user communicating the validation rule that is not being complied with, as well as input 
masks for the variables that require it, such as dates. It will be possible to proceed to fill 
the CRF in successive times, with the consequent saving at each moment. 
 
 
A.9 
AMENDMENTS 
 
The Investigational Product, Protocol, CRF, informed consent or other subject 
information, or other clinical investigation documents may be amended during the clinical 
investigation if necessary. In this case a justification statement will be included with each 
amended section of a document. Proposed amendments to the Protocol will be agreed 
between the sponsor and the coordinating investigator. They should be notified to and 
approved by the CEIM and regulatory authorities if required and the version number and 
date of the amendments will be documented. 
 
For non-substantive changes that do not affect the rights, safety, and welfare of human 
subjects and are not related to the objectives or endpoints of the clinical investigation, 
notification to CEIM and, where appropriate, to regulatory authorities will be sufficient. 
 
 
 
 

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A.10 DEVIATIONS FROM THE CLINICAL RESEARCH PLAN 
 
Reports of deviations will be communicated to CEIM, if the deviation affects the rights, 
safety and welfare of the subjects or the scientific integrity of the clinical investigation. 
In such cases, written approval will be obtained from CEIM. 
 
In emergency circumstances, deviations from the protocol to protect the rights, safety, 
and welfare of human subjects may proceed without prior approval of the sponsor and 
the CEIM. Such deviations should be documented and notified to the sponsor and 
CEIM as soon as possible. 
 
 
A.11 PRODUCT ACCOUNTING 
 
Access to investigational products will be controlled and used only in clinical research 
and in accordance with the protocol. 
The sponsor will maintain records to document the physical location of investigational 
products from the time they are shipped to participating sites until they are returned or 
disposed of. 
The principal investigator or an authorized designee should maintain records 
documenting the receipt, use, return, and disposal of investigational products. Such 
records shall include: date received, product identification, expiration and use date, 
subject identification, withdrawal date if applicable, and return date for products that were 
not used or expired. 
A.12 COMPLIANCE STATEMENT 
 
The clinical investigation will be carried out in accordance with the ethical principles set 
forth in the Declaration of Helsinki, will be conducted in compliance with this standard 
and any regional or national regulations as appropriate. 
 
The clinical investigation will commence when the favorable opinion of the CEIM and 
the authorization of the AEMPS have been obtained as well as having fulfilled any 
additional requirements imposed. 
 
It will have a civil liability insurance that guarantees the Promoter's Civil Liability derived 
from the clinical research, for the damages caused to the participating participants that 
fulfills the legal requirements established in the Spanish legislation. In addition, the Civil 
Liability of the investigator and his collaborators and of the Owner of each hospital where 
it is carried out is also covered. 
 
 
A.13 INFORMED CONSENT PROCESS 
 
Informed consent must be obtained from the participant in writing prior to any specific 
clinical research procedure, except when special circumstances apply. The principal 

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investigator or his/her assigned collaborator is responsible for the process of obtaining 
consent. 
 
It should contain all aspects of the clinical investigation that are relevant to the subject's 
decision to participate. It should avoid any coercion or undue inappropriate influences or 
inducements on the participant to participate. Do not disregard or appear to disregard the 
legal rights of the subjects. Use the subject's own language in clear and understandable 
terms. 
 
The subject will be provided sufficient time to read and understand the informed consent 
form and consider participation in the clinical investigation. It will include the dated 
handwritten signatures of the subject and the principal investigator or his/her authorized 
designee responsible for executing the informed consent process. The subject will be 
provided with a copy of the signed and dated form and any other written information. 
 
Special circumstances for informed consent are as follows. 
 
- Subjects who need legally authorized representatives. The legally authorized 
representative can give informed consent only if a subject is incapable of making the 
decision to participate and, the subject must also be informed about the clinical 
investigation to the extent of his or her capacity to understand. 
 
- Subject unable to read or write: must be obtained using a supervised oral process, an 
independent witness must be present during the process. It should be read aloud and 
explained to the prospective subject or his or her legally authorized representative, and 
whenever possible, either should personally sign and date the form. The witness also 
personally signs and dates the form attesting that the information was accurately 
explained and that consent was freely given. 
 
- Urgent treatments: Urgent treatments are not foreseen but if this is the case, if the 
patient's prior consent is not possible due to the patient's medical condition, the signature 
of his/her legally authorized representative will be requested. The participant or his/her 
legally authorized representative will be informed as soon as possible and will be asked 
to give consent as soon as his/her condition permits. 
 
 
A.14 ADVERSE EVENTS, ADVERSE EFFECTS OF THE PRODUCT AND 
PRODUCT DEFICIENCIES 
 
 
Definitions 
 
Adverse Event (AE) 
An adverse event (AE) is any unintended medical episode, unanticipated illness or injury, 
or any clinical sign, including an abnormal laboratory finding, in subjects, users, or any 
other person, whether or not related to the investigational product. Includes medical 
device or control; includes events related to the procedures used. 
 
 
Serious Adverse Event (SAE) 

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Any adverse event that: 
- Leads to death 
- Serious deterioration in health status that results in: 
1. produced a life-threatening illness or injury; 2. 
2. 
Permanent damage to bodily structure or function  
3. 
Requires hospitalization or prolongation of hospitalization 
4. 
Unplanned medical/surgical intervention to avoid treatment or life-
long injury to a bodily structure or function. 
- Results in fetal damage, congenital anomaly or birth defect.  
 
 
For reporting purposes, adverse events that are considered medically significant, even if 
they do not meet the above criteria, such as those that put the patient at risk or require 
intervention to prevent any of the above outcomes, will also be treated as serious.  
 
 
Adverse Device Event (ADE) 
An adverse event related to the use of an investigational medical device. This definition 
includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or any malfunction of the investigational medical 
device. It includes any adverse event resulting from an error in the use of the 
investigational medical device. 
 
Serious Adverse Device Event (ADE) 
 
An adverse event of the product that has produced any consequence characteristic of a 
serious adverse event. 
 
 
Unexpected serious adverse device event (USADE) 
It is an adverse event of the product that due to its nature, incidence, intensity or 
consequence has not been identified in the updated version of the risk analysis report. 
 
Product deficiencies 
All deficiencies of a medical device related to: identity, quality, durability, reliability, 
safety/performance, malfunction/error of use, inadequate labeling.  
 
Noticeable events 
They are any AGEs; any deficiency of a medical device that could have led to an AGE 
if timely action had not been taken, no intervention had been made, or in less fortunate 
circumstances; or new findings and updates on reported events. 
 
Expedited notification 
The sponsor will notify the AEMPS of all serious adverse events whether they are related 
to the investigational medical device or not, whether they occur in Spain or in other states 
and whether they have occurred in the authorized clinical investigation or in other clinical 
investigations or in a different context of use, provided that such medical devices are not 
marketed in Spain. 

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For marketed products, including the medical device used as a control, the requirements 
of the European system of vigilance of medical devices will be taken into account in order 
to avoid possible duplications in the notification. 
 
 
Expedited Notification Deadlines 
The maximum notification period will be 15 calendar days from the moment the sponsor 
became aware of the serious adverse event. When the serious adverse event has caused 
the death of the subject, or endangered his life, the sponsor shall inform the AEMPS 
within a maximum of 7 calendar days from the moment the sponsor became aware of the 
case. Such information should be completed, as far as possible, within the following 8 
days. 
 
Recording and reporting of adverse events and incidents 
 
All adverse events and incidents occurring from the inclusion of the patient in the study 
(i.e., from the signing of the consent form) until the end of the planned follow-up per 
patient should be recorded in the CRF by the investigator noting their characteristics. All 
adverse events should be recorded using medical terminology. 
 
 
Procedures for reporting serious and unexpected adverse events and adverse 
incidents. 
All serious adverse events and adverse incidents should be reported to the sponsor's 
safety committee. This will include, but is not limited to 
- Death from any cause 
- Life-threatening hemorrhage 
- Intracranial hemorrhage 
- Epidural hematoma 
- Meningitis 
- Cerebrovascular accident 
- Deep thrombocytopenia (platelet count <50,000/mm3) 
 
Any adverse and/or unexpected AAG and incident should be reported to the sponsor's 
designated CRO (TRIDE) within 24 working hours of knowledge of the event. All 
information related to SAEs will be reported by e-mail using the SAE and adverse event 
forms of the CRD of the investigation, which must be signed by the investigator himself 
or a collaborating member of his team.  
 
To report an incident, it is necessary that it is associated with a medical device or with the 
information provided with the medical device and that the incident is such that it has 
resulted in death or serious deterioration in health, or that if it occurs again it could cause 
them.  
 
The types of adverse incidents that should be reported are as follows:  
1. Those that result in death  
2. Those resulting in serious deterioration of the patient's, user's or other person's health 
status, such as:  
- 
Life-threatening illness or injury  

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- 
Permanent impairment of a bodily function or permanent damage to a bodily 
structure. 
- 
A process that requires medical or surgical intervention to prevent permanent 
impairment of a bodily function or permanent damage to a bodily structure.  
3. Potential incidents, which are those that could have resulted in death or serious 
deterioration of health, but which have not occurred due either to fortunate circumstances 
or to the intervention of healthcare personnel.  
Incidents involving medical devices should be reported to the medical device vigilance 
point of the Autonomous Community. The communication should be made as soon as 
possible. It can be done by fax or by post. In the case of very serious incidents, it should 
be done as quickly as possible, by fax, until the means are available to send the 
communication "on line"; if fax is not available, it can be notified by telephone, sending 
the form by post afterwards. The form available in the CRF shall be used for this purpose. 
 
 
A.15 VULNERABLE POPULATION  
 
The clinical research will be carried out in participants whose diagnosis leads to an 
indication to receive the treatment under study within the general population and the 
inclusion of vulnerable population is not contemplated. 
 
A.16 SUSPENSION OR EARLY DISCONTINUATION OF CLINICAL 
RESEARCH 
 
The sponsor may suspend or terminate early either a clinical investigation at an individual 
investigational site or the entire clinical investigation for significant and documented 
reasons. 
The national coordinator, a principal investigator, IRB/IEC or regulatory authority may 
suspend or terminate participation in the clinical investigation at the investigational sites 
for which it is responsible. 
If suspicion of unacceptable risk to subjects arises during the clinical investigation, or 
when instructed to do so by the IRB/IEC or regulatory authority, the sponsor should 
suspend the clinical investigation while the risk is being determined. The sponsor should 
discontinue the clinical investigation if an unacceptable risk is confirmed. 
The sponsor should consider discontinuing or suspending the participation of an 
investigational site or an individual investigator if monitoring or auditing identifies 
serious or repeated deviations by an investigator. 
If suspension or early discontinuation occurs, the party so disposing should justify its 
decision in writing and promptly inform the other parties with whom it is in direct 
communication. The principal investigator and sponsor should keep each other informed 
of any communication received from either the CEIM or the regulatory authority. 
If, for any reason, the sponsor suspends or discontinues research at an individual 
investigational site early, the sponsor should inform the responsible regulatory authority 
as appropriate and ensure that the principal investigator or sponsor notifies the CEIM. If 
the suspension or early discontinuation was in the interest of safety, the sponsor should 
inform all other principal investigators. 
 
If suspension or early discontinuation occurs, the sponsor should remain responsible for 
providing the resources to fulfill the obligations of the protocol and existing agreements 
for follow-up of the subjects included in the clinical investigation and the principal 

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investigator or his authorized designee should promptly inform the subjects included at 
his investigational site, if appropriate. The method and timing of this communication will 
depend on the circumstances and perceived risks. 
When the sponsor concludes an analysis of the reason for suspension, implements the 
necessary corrective actions, and decides to lift the temporary suspension, the sponsor 
should inform the principal investigators, the IRB/IECs, and, where appropriate, the 
regulatory authorities of the justification and provide them with the relevant data 
supporting this decision. The concurrence of the IRB/IEC and, where appropriate, the 
regulatory authorities should be obtained prior to resumption of the clinical investigation. 
If the subjects have been informed of the suspension, the principal investigator or his/her 
authorized designee should inform them of the reasons for resumption. 
 
 
A.17 PUBLICATION POLICY 
 
The sponsor expressly agrees to publish the results of the clinical investigation, whether 
positive or negative. 
 
 
 
 

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A.18 BIBLIOGRAPHY 
 
 
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16. Chan CW, Peng P. Failed back surgery syndrome. Pain Med 2011; 12: 577-606. 
 
17. Schofferman J, Reynolds J, Herzog R, et al. Failed back surgery: Etiology and diagnostic 
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treatment of failed back surgery syndrome: A case series of 100 patients. Acta Neurochir 
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findings, and long-term results: A report of 182 operative treatments. Spine 1996; 21: 
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27. North RB, Campbell JN, James CS, et al. Failed back surgery syndrome: 5-year follow-
up in 102 patients undergoing repeated operation. Neurosurgery 1991; 28: 685-90.  
 
28. Chun-jing H, Hao-xiong N, Jia-xiang N. The application of percutaneous lysis of epidural 
adhesions in patients with failed back surgery syndrome. Acta Cir Bras 2012; 27: 357-
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29. Manchikanti L, Singh V, Cash KA, et al. A comparative effectiveness evaluation of 
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surgery syndrome: A randomized, equivalence controlled trial. Pain Physician 2009; 12: 
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30. Manchikanti L, Singh V, Cash KA, et al. Assessment of effectiveness of percutaneous 
adhesiolysis and caudal epidural injections in managing lumbar post surgery syndrome: 
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31. North RB, Kidd DH, Farrokhi F, et al. Spinal cord stimulation versus repeated 
lumbosacral spine surgery for chronic pain: A randomized, controlled trial. Neurosurgery 
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32. Van Buyten JP. Neurostimulation for chronic neuropathic back pain in failed back 
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33. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150(699):971-9 
 
34. Wong SS, Chan CW, Cheung CW. Spinal cord stimulation for chronic non-cancer pain: 
a review of current evidence and practice. Hong Kong Med J 2017;23: 517-23. 
 
35. Kumar K, Taylor RS, Jacques L, et al. Spinal cord stimulation versus conventional 
medical management for neuropathic pain: A multicentre randomised controlled trial in 
patients with failed back surgery syndrome. Pain 2007; 132:179-88. 
 
36. Kapural L, Yu C, Doust MW, et al. Comparison of 10-kHz high-frequency and traditional 
low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: 24-
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37. Bala MM, Riemsma RP, Nixon J, et al. Systematic review of the (cost-) effectiveness of 
spinal cord stimulation for people with failed back surgery syndrome. Clin J Pain 2008; 
24: 741-56. 
 
38. Kumar K, Rizvi S. Cost-effectiveness of spinal cord stimulation therapy in management 
of chronic pain. Pain Med 2013; 14: 1631-49. 
 
39. Farber SH, Han JL, Elsamadicy AA, et al. Long-term Cost Utility of Spinal Cord 
Stimulation in Patients with Failed Back Surgery Syndrome. Pain Physician. 2017; 20: 
E797-805. 
 
40. Lad SP, Babu R, Bagley JH, et al. Utilization of spinal cord stimulation in patients with 
failed back surgery syndrome. Spine (Phila Pa 1976) 2014; 39: E719-E27. 
 
41. Song JJ, Popescu A, Bell RL. Present and potential use of spinal cord stimulation to 
control chronic pain. Pain Physician 2014; 17: 235-46. 
 
42. Deer TR, Mekhail N, Provenzano D, et al. The appropriate use of neurostimulation of the 
spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic 
diseases: 
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43. Mailis-Gagnon A, Furlan AD, Sandoval JA, et al.  Spinal cord stimulation for chronic 
pain. Cochrane Database Syst Rev 2004:CD003783. 
 
44. North JM, Hong KJ, Cho PY. Clinical Outcomes of 1 kHz Subperception Spinal Cord 
Stimulation in Implanted Patients With Failed Paresthesia-Based Stimulation: Results of 
a Prospective Randomized Controlled Trial. Neuromodulation  2016; 19: 731-7. 
 
45. Abejon D, Cameron T, Feler C, et al. Electric parameters optimization in spinal cord 
stimulation. Study in conventional nonrechargeable systems. Neuromodulation 2010; 13: 
281–6. 
 

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46. Alo KM, Yland MJ, Kramer DL, et al. Computer assisted and patient interactive 
programming of dual octrode spinal cord stimulation in the treatment of chronic pain. 
Neuromodulation 1998; 1: 30–45. 
 
47. North RB, Kidd DH, Olin J, et al. Spinal cord stimulation with interleaved pulses: a 
randomized, controlled trial. Neuromodulation 2007; 10: 349–57. 
 
48.  Holsheimer J, Buitenweg JR, Das J, et al. The effect of pulse width and contact 
conﬁguration on paresthesia coverage in spinal cord stimulation. Neurosurgery 2011; 68: 
1452–61. 
 
49. Yearwood TL, Hershey B, Bradley K, et al. Pulse width programming in spinal cord 
stimulation: a clinical study. Pain Physician 2010; 13: 321–35. 
 
50. North RB, Ewend MG, Lawton MT, et al. Spinal cord stimulation for chronic, intractable 
pain: superiority of “multi-channel” devices. Pain 1991; 44: 119–30. 
 
51. Benyamin R, Kramer J, Vallejo R. A case of spinal cord stimulation in Raynaud’s 
Phenomenon: can subthreshold sensory stimulation have an effect? Pain Physician 2007; 
10: 473–8. 
 
52. Eddicks S, Maier-Hauff K, Schenk M, M€uller A, Baumann G, Theres H. Thoracic spinal 
cord stimulation improves functional status and relieves symptoms in patients with 
refractory angina pectoris: the ﬁrst placebo-controlled randomised study. Heart 2007; 93: 
585–90. 
 
53. Melzack, R., Katz, J. y Jeans, M.E. (1985).The role of compensation in chronic pain: 
Analysis using a new method of scoring the McGill Pain Questionnaire. Pain, 23, 101-
112. 
 
54. Fairbank JCT, Couper J, Davies JB. The Oswestry low back pain questionnaire 
Physiotherapy 1980; 66: 271-3. 
 
55. Wille F, Breel JS, Bakker EW, et al. Altering Conventional to High Density Spinal cord 
Stimulation: An Energy Dose-Response relationship in Neuropathic Pain Therapy. 
Neuromodulation 2017; 20: 71-80.  
 
 
 
 
 
 
 
 
 
 
 

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ANNEX 1 ABBREVIATIONS AND DEFINITIONS  
 
 
CEIM: Comité Ético de Investigación / Research Ethics Committee 
CRF: Clinical data Research Form 
OC: Oswestry questionaire 
CRO: Contract Research Organization 
EMC: Estimulación medular convencional / Conventional spinal cord stimulation 
EME: Estimulación medular sistema EVOLVE / Spinal cord stimulation EVOLVE 
system 
EVOLVE: Standardized guide to a programming flow of Medtronic® spinal 
neurostimulation systems: SureScan ™ MRI and AdaptativeStim ™. 
FBSS: Failed back surgery syndrome 
IRB/IECs: Institutional Review Board / Institutional Ethics Committee 
VAS: Visual Analogue Scale 
 
 
 

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ANNEX II VISUAL ANALOG SCALE 
 
VISUAL ANALOG PAIN INTENSITY SCALE 
 
 
 
Indicate on this scale the intensity of your pain, where 0 is no pain at all and 10 is the 
most unbearable pain imaginable. 
 
 
 
0        1          2         3         4        5         6         7        8          9        10 
  
 
 
 
 
 
 
 
 
 
 
No pain                                                                                            Unbearable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ANNEX III OSWESTRY QUESTIONNAIRE 
 
 
OSWESTRY QUESTIONNAIRE ON DISABILITY ASSOCIATED WITH LOW 
BACK PAIN 
Thank you for completing the questionnaire. It is designed to tell us how low back pain 
affects your ability to function in daily life. 
Choose the option that applies to you at this time to answer each section below. 
Selecciona la opción que mejor describa su problema en este momento. 
 
Section 1. Pain intensity 
o I can handle pain without taking painkillers [0 points]. 
o The pain is severe but I manage without taking painkillers [1 point]. 
o Painkillers relieve my pain completely [2 points]. 
o Painkillers give me some pain relief [3 points]. 
o Painkillers barely relieve my pain [4 points]. 
o Painkillers do not relieve my pain and I do not take them [5 points]. 
 
Section 2. Personal care 
o I can manage on my own without it increasing my pain [0 points]. 
o I can manage on my own but it increases my pain [1 point]. 
o Self-care causes me pain and I have to do it slowly and carefully [2 points]. 
o I need some help but I manage to do most things on my own [3 points]. 
o I need help to do most things [4 points]. 
o I can't get dressed, have trouble washing myself and often stay in bed [5 
points]. 
 
Section 3. Lifting weights 
o I can lift heavy objects without increasing pain [0 points]. 
o I can lift heavy objects but it increases my pain [1 point]. 
o Pain prevents me from lifting heavy objects off the floor, but I can lift heavy 
objects if they are in a comfortable place (e.g., on a table) [2 points]. 
o Pain prevents me from lifting heavy objects, but I can lift light to medium 
objects if they are in a comfortable place [3 points] 
o I can only lift very light objects [4 points]. 
o I am unable to lift or carry any objects [5 points]. 
 
Section 4. Walking 
o Pain does not prevent me from walking any distance [0 points]. 
o Pain prevents me from walking more than one kilometer [1 point]. 
o Pain prevents me from walking more than 500 meters [2 points]. 
o Pain prevents me from walking more than 250 meters [3 points]. 
o I can only walk with a cane or crutches [4 points]. 
o I stay in bed most of the time and have to crawl to the bathroom [5 points]. 

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Section 5. Sitting.  
o I can sit in any type of chair for as long as I want [0 points]. 
o I can only sit in my favorite chair as long as I want [1 point]. 
o Pain prevents me from sitting for more than an hour [2 points]. 
o Pain prevents me from sitting for more than half an hour [3 points]. 
o Pain prevents me from sitting for more than 10 minutes [4 points]. 
o The pain prevents me from sitting [5 points]. 
Section 6. Standing 
o I can stand as long as I want without increasing pain [0 points]. 
o I can stand as long as I want but it increases my pain [1 point]. 
o Pain prevents me from standing for more than one hour [2 points]. 
o Pain prevents me from standing for more than half an hour [3 points]. 
o Pain prevents me from standing for more than 10 minutes [4 points]. 
o The pain prevents me from standing [5 points]. 
Section 7. Sleeping 
o Pain does not prevent me from sleeping well [0 points]. 
o I can only sleep if I take pills [1 point]. 
o Even taking pills I sleep less than 6 hours [2 points]. 
o Even taking pills I sleep less than 4 hours [3 points]. 
o Even taking pills I sleep less than 2 hours [4 points]. 
o The pain totally prevents me from sleeping [5 points]. 
Section 8. Sex life 
o My sexual activity is normal and does not increase my pain [0 points]. 
o My sexual activity is normal but increases my pain [1 point]. 
o My sexual activity is almost normal but my pain is greatly increased [2 points]. 
o My sexual activity has been very limited because of the pain [3 points]. 
o My sexual activity is almost nil because of the pain [4 points]. 
o The pain prevents me from any kind of sexual activity [5 points]. 
Section 9. Social life 
o My social life is normal and does not increase my pain [0 points]. 
o My social life is normal but increases my pain [1 point]. 
o The pain does not have a major effect on my social life, but it does impede 
my more energetic activities such as dancing [2 points] 
o The pain has limited my social life and I do not go out as often [3 points]. 
o The pain has limited my social life to the home [4 points]. 
o I have no social life because of the pain [5 points]. 

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Section 10. Travelling 
o I can travel anywhere without increasing my pain [0 points]. 
o I can travel anywhere, but it increases my pain [1 point]. 
o Pain is severe, but I can endure trips of more than 2 hours [2 points]. 
o Pain limits me to trips of less than one hour [3 points]. 
o Pain limits me to short, necessary trips of less than half an hour [4 points]. 
o Pain prevents me from traveling except to go to the doctor or hospital [5 
points].