Evaluating the Effect of Spinal Cord Stimulation Frequency on Fast-Acting Sub-perception Therapy (FAST) for Chronic Pain

Prospective Single-centre, Double-blind, Randomised Study to Evaluate the Effect of Spinal Cord Stimulation Frequency on wash-in/Wash-out Time and Clinical Outcomes in Subjects Using Fast-Acting Sub-perception Therapy (FAST) for Chronic Pain

The study design is prospective, post-market, exploratory, single-centre, rate randomised, double-blinded (subject, evaluator blinded; programmer un-blinded). The study is designed to evaluate the wash-in and wash-out time of FAST (Fast Acting Sub-perception Therapy) at 90 Hz and various frequencies above and below 90 Hz.

A prospective study design will eliminate the bias associated with case selection in a retrospective review and will ensure that identical procedures are followed for data capture and review.

Randomization of rates will be used to minimise the sequence effects and the impact of carryover effects, as well as addressing issues that may be related to order effect.

The electronic diary will be used to log the subjects' pain intensity and medication usage. Additionally, the numerical rating scale for measuring pain intensity is a validated measure and has been used in other randomized controlled trials to measure the outcomes of spinal cord stimulation (SCS).

The electronic real-time NRS (Numerical rating score) recording will be used to log the subjects' pain intensity and time during wash-in evaluation session.

This study aims to evaluate pain relief and wash-in/wash-out frequency sensitivity using FAST at different stimulation rates. The different randomization period included in the study design allows for comparing these treatments using one of the stimulation rates as an active control.

Chronic Pain Background

Chronic intractable pain is a significant worldwide health issue, which consumes considerable healthcare resources and heavily impacts the quality of life for many patients. It is often defined as pain persisting for at least 6 months and not responding to conservative treatment(s). Chronic pain may be induced by current or past nerve injury and causes significant disability. People affected by such condition often experience reduced health-related quality of life, reduced ability to engage in activities of daily living, depression, sleep disturbances and weight gain due to the adoption of a sedentary lifestyle.

Typical entry into the pain management continuum includes over-the-counter medications, followed by physical therapy and complementary medicine. Interventional Pain management, Interdisciplinary pain management and surgery are attempted next and are often followed by long-term oral opioids intake. Active implantable options, including Spinal Cord Stimulation (SCS), lie within the continuum of chronic pain therapies and can be recommended as an alternative to long-term opioids intake (as recommended by National Institute of Clinical Excellence- NICE).

Spinal Cord Stimulation (SCS)

SCS refers to the application of small amounts of electrical energy, often via wires (a.k.a. "leads") to stimulate nerves in the spinal cord and reduce chronic pain symptoms. SCS is a less invasive treatment option for chronic pain that has generally been reserved for patients who have failed multiple, and sometimes all, conservative chronic pain therapies. With SCS, an implanted pulse generator (IPG) delivers electrical current to leads implanted in the epidural space at specific spinal level. Electrical currents stimulates nerves and can be shaped to optimise stimulation of fibres innervating the painful locations, thereby reducing pain sensation.

For decades, paresthesia-based SCS has been used to treat chronic pain. The classic approach typically uses frequencies between 40-100 Hz and enables a relatively straightforward identification and energy-efficient stimulation of the so-called therapeutic "sweet-spot". However, a potential drawback of this method of treatment is that patients using paresthesia-based SCS must endure paresthesias ("tingling") which, although may not always be bothersome and even pleasant to some, is an aspect that some may prefer to avoid.

Although, within the last 10 years, SCS device technologies have expanded considerably. One example is the introduction of higher stimulation frequency (i.e., 10 kHz) and amplitudes below perception threshold, enabling patients to obtain pain relief without experiencing paresthesia. This approach is known as sub-perception SC. However, this method is very energy-intensive, requires patients to recharge every 1-2 days and exhibits a slow "wash-in" time (i.e., the time between therapy activation and relief from pain). Conventional sub-perception methodologies have the desirable property of not requiring the patient to feel paresthesia but have some notable drawbacks. In particular, (1) patients leave the clinic still awaiting relief and hoping that one of the programs provided will be effective, (2) the sweet-spot is assessed via a "blind" search, an approach that limits the number of program settings testable on each patient and calling into question whether or not the final settings are optimal, (3) and in many cases the programs require much more energy than a paresthesia-based program.

As part of an effort to improve patients' experience and outcomes associated with the utilization of sub-perception SCS, the investigators hypothesised that there might be a putative relationship between the following: a) the specific location in which a sub-perception stimulation field is most effective and b) the paresthesia that overlaps the physical area(s) of pain as reported by each patient. Evaluation of this hypothesis led the investigators to develop a novel approach for implementation of sub-perception SCS, which is termed "Fast Acting Sub-perception Therapy" (FAST). This new methodology offers all the advantages provided by both paresthesia- and sub-perception-based SCS while simultaneously mitigating the potential downsides typically associated with each of these modalities when they are applied independently.

Study objectives and Endpoints

Primary objective

The primary objective of this study is to evaluate the wash-in/wash-out times of Fast-Acting Sub-perception Therapy (FAST) and best clinical outcomes as measured by mean reported pain on Numerical Rating Scale at 90 Hz and with frequencies above and below 90 Hz.

Secondary objective

The secondary objective will be to investigate the effect on functionality, quality of life, therapy longevity (3 and 6-month) and adverse events in the study population.

Primary endpoint

There are no Primary Endpoints for this exploratory study.

Exploratory endpoint

The following exploratory endpoints will be collected in this study:

• Wash-in time of overall pain intensity (RT-NRS) of each Rate Randomization (A, B, C, D)
• Wash-out time of lower back, legs pain and overall pain intensity (ED-NRS) of each Rate Randomization (A, B, C, D)
• Change in average lower back, legs pain and overall pain intensity (ED-NRS) from Baseline to end of each Randomization (A, B, C, D) and Long-Term Follow-up periods
• Treatment Satisfaction at end of each Rate Randomization (A, B, C, D) and Long-Term Follow-up periods (PSWT)
• Global impression of change at end of each Rate Randomization (A, B, C, D) and Long-Term Follow-up periods (PGIC)
• Change in disability from Baseline to end of each Rate Randomization (A, B, C, D) and Long-Term Follow-up periods (ODIv2.1a)
• Change in Quality of life from Baseline to end of each Rate Randomization (A, B, C, D) and Long-Term Follow-up periods (EQ-5D-5L)
• Change in sleep quality from Baseline to end of each Rate Randomization (A, B, C, D) and Long-Term Follow-up periods (PSQ3)
• Subject preferred program at Long-Term Follow-up period (Preference Questionnaire)
• Pain/paresthesia overlap for each tested configuration at Rate Randomization (A, B, C, D) and Long-Term Follow-up periods (Pain/Paresthesia drawing

Inclusion Criteria:

• The subject is between 18 and 75 years of age when written informed consent is obtained.
• Complaint of persistent or recurrent low back pain, with or without equal or lesser leg pain, for at least 90 days prior to Screen.
• Received at least 90 days of documented pain management care to address the primary pain complaint, prior to Screening (e.g. medication, physical therapy.)
• Diagnosed with chronic neuropathic pain of the low back and legs (of neuropathic origin only).
• Eligible candidate for SCS from a psychological and psychiatric standpoint as determined prior to Baseline Visit, per site's routine screening process No back surgery within 6 months prior to Screening.
• Average low back pain intensity, during the position/activity, which routinely causes worst pain, of 5 or greater on a 0-10 numerical rating scale during Baseline period based on eDiary.
• If taking prescription opioids for primary chronic pain complaint (low back and/or leg pain), must have been on a stable prescription (same drug(s) and dose(s)) 30 days prior to Screening to a total of less than 180 mg Oral Morphine equivalent.
• Willing and able to comply with all protocol-required procedures and assessments/evaluations (e.g. willing to comply with opioid prescription lock from the Baseline visit through End of Rate Randomization and protocol required stimulation parameter locks, complete daily eDiary).
• If female of childbearing potential: not pregnant, as evidenced by a negative pregnancy test at Screening.
• Subject signed a valid, IRB-approved informed consent form (ICF) provided in English.

Exclusion Criteria:

• Significant cognitive impairment at Screening that, in the opinion of the Investigator, would reasonably be expected to impair the study candidates to participate in the study
• Have untreated major psychiatric comorbidity, serious drug related behaviour issues.
• Previous spinal cord stimulation trial or is already implanted with an active implantable device(s) (e.g. pacemaker, drug pump, implantable pulse generator).
• Participating (or intends to participate) in another drug or device clinical trial that may influence the data that will be collected for this study
• Currently on any anticoagulant medications that cannot be discontinued during perioperative period
• Current condition associated with risk of immunocompromised that might increase risk of infection during study duration.
• A female who is pregnant, is breastfeeding, or is of childbearing potential and planning to get pregnant during the study or not using adequate contraception.
• Primary pain complaint of vascular origin (e.g. peripheral vascular disease). Spinal pain secondary to neoplasm, infection, autoimmune disorder with spinal involvement, or a spinal metabolic disorder.
• Clinically significant lumbosacral stenosis which would interfere with lead placement
• Prior history of lumbar-sacral spine fusion
• Any pain-related diagnosis or medical/psychological condition that, in the clinician's best judgment might confound reporting of study outcomes (e.g. pelvic pain, angina pain, chronic migraine.
• Radiographic evidence of spinal instability requiring fusion
• Terminal illness with anticipated survival 1 year.