ReActiv8 Implantable Neurostimulation System for Chronic Low Back Pain

Study Overview
=================
Brief Summary
-----------------
The purpose of this trial is to evaluate the safety and efficacy of ReActiv8 for the treatment of adults with Chronic Low Back Pain when used in conjunction with medical management.

Official Title
-----------------
ReActiv8 Implantable Neurostimulation System for Chronic Low Back Pain (ReActiv8-B)

Conditions
-----------------
Chronic Low Back Pain

Intervention / Treatment
-----------------
* Device: ReActiv8 Implantable Stimulation System (Patient Appropriate Stimulation)
* Device: ReActiv8 Implantable Stimulation System (Low Stimulation)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥22 years, ≤75 years Chronic Low Back Pain that has persisted >90 days prior to the baseline visit. Continuing low back pain despite >90 days of medical management. Qualifying pain score. Qualifying disability score. Evidence of lumbar multifidus muscle dysfunction. Be willing and capable of giving Informed Consent. Ability to comply with the instructions for use and to operate ReActiv8, and to comply with this Clinical Investigation Plan. Suitable for ReActiv8 surgery as determined by the implanting physician prior to inclusion. Exclusion Criteria: BMI > 35 Back Pain characteristics: Any surgical correction procedure for scoliosis at any time, or a current clinical diagnosis of scoliosis. Lumbar spine stenosis, as defined by an anterior-posterior diameter of the spinal canal of <10mm in subjects with lower extremity pain. Neurological deficit possibly associated with the back pain (e.g. foot drop). Back pain due to pelvic or visceral reasons (e.g.: endometriosis or fibroids) or infection (e.g.: post herpetic neuralgia). Back pain due to inflammation or damage to the spinal cord or adjacent structures (e.g. arachnoiditis or syringomyelia). Pathology seen on MRI that is clearly identified and is likely the cause of the CLBP that is amenable to surgery. Back pain due to vascular causes such as aortic aneurysm and dissection. Any current indication for back surgery according to local institutional guidelines, or has indication for back surgery but cannot undergo surgery for other reasons. Leg pain described as being worse than back pain, or radiculopathy (neuropathic pain) below the knee. Source of pain is the sacroiliac joint as determined by the Investigator. Drug use. Surgical and other procedures exclusions. Any prior diagnosis of lumbar vertebral compression fracture, lumbar pars fracture, or lumbar annular tear with disc protrusion that is amenable to surgery. Planned surgery. Co-morbid chronic pain conditions. Other clinical conditions. Psycho-social exclusions. Protocol compliance exclusions. General exclusions.

Ages Eligible for Study
-----------------
Minimum Age: 22 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br> | Device: ReActiv8 Implantable Stimulation System (Patient Appropriate Stimulation)<br>* ReActiv8 implanted and configured to deliver stimulation at a patient-appropriate level, and participants instructed to deliver stimulation in two 30-minute sessions per day.<br>|
| Experimental: Control<br> | Device: ReActiv8 Implantable Stimulation System (Low Stimulation)<br>* ReActiv8 implanted and configured to deliver low stimulation, and participants instructed to deliver stimulation in two 30-minute sessions per day.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder Rate of Low Back Pain With No Increase in Pain Medications | Comparison of responder rates for low back pain VAS between Treatment and Control groups. The Primary Efficacy Endpoint is a comparison of responder rates between Treatment and Control groups, where a responder is a participant with ≥30% reduction from baseline in average low back pain VAS, without any increase from baseline in pain medications and/or muscle relaxants for any reason including non low back pain reasons. The instrument used for evaluating pain is the continuous Visual Analog Scale (VAS) comprised of a horizontal line 10 cm in length, anchored by 2 verbal descriptors, where zero indicates no pain and 10 indicates worst imaginable pain. The value reported is a 7-day average low back pain. Any increase in dosage of a pain medication or any new pain medication taken for any reason counts as an increase in medications. | 120 Days | 
| Mean Change in Low Back Pain VAS | Comparison of change in LBP VAS (120 days from baseline) between the Treatment and Control groups. The instrument used for evaluating pain is the continuous Visual Analog Scale (VAS) comprised of a horizontal line 10 cm in length, anchored by 2 verbal descriptors, where zero indicates no pain and 10 indicates worst imaginable pain. The value reported is a 7-day average low back pain. A change to a lower score (negative value) indicates improvement. | 120 Days | 
| Cumulative Proportion of Responders Analysis (CPRA) for the Primary Endpoint to Compare Participants Responses Over a Full Range of Response Levels | The CPRA, which was prespecified in the clinical protocol and statistical analysis plan prior to the start of the trial, was performed using the same data as used for the primary endpoint analysis and was included as part of the primary endpoint analysis | 120 Days | 
| Serious Device and/or Procedure Related Adverse Event Rate | The primary safety assessment is of serious device and/or procedure related adverse events in all participants at 120 days. The 8 events reported below are 6 implant site pocket infections, 1 intra-operative upper airway obstruction, and 1 non-radicular, focal numbness on the surface of the thigh. | 120 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Oswestry Disability Index (ODI) | Comparison of change in ODI (120 days from baseline) between Treatment and Control groups. ODI is reported as a score from 0 to 100%, where 0%-20% indicates minimal disability, 21%-40% indicates moderate disability, 41%-60% indicates severe disability, 61%-80% indicates crippled, and 81%-100% indicates bedbound or an exaggeration of symptoms. A change to a lower score (negative value) indicates improvement. | 120 Days | 
| Change in European Quality of Life Score on Five Dimensions (EQ-5D) | Comparison of change in EQ-5D (120 days from baseline) between Treatment and Control groups. The EQ-5D Index is scored on a scale of -0.594 to 1.00, with a score of 1.00 indicating full health. A change to a higher score (positive value) indicates improvement. | 120 Days | 
| Change in Percent Pain Relief (PPR) | PPR is a patient-reported percent of pain relief at 120 days compared to the pain at baseline, where 0% indicates no pain relief compared to baseline, and 100% indicates complete pain relief compared to baseline. | 120 Days | 
| Subject Global Impression of Change (SGIC) | A questionnaire completed with the following item: Since I enrolled in the study, my overall status is 1) Very much improved, 2) Much improved, 3) Minimally improved, 4) No change, 5) Minimally worse, 6) Much worse, 7) Very much worse | 120 Days | 
| Resolution of Back Pain (VAS ≤2.5 cm) | Resolution of back pain (remitter rate) was defined as a participant with 7-day average low back pain VAS ≤2.5 cm on the 10 cm VAS. | 120 Days | 
| LBP VAS Responder Rate at One Year | A responder is a participant with ≥30% reduction from baseline in average low back pain VAS, without any increase from baseline in pain medications and/or muscle relaxants for any reason including non low back pain reasons. After the 120 day visit, participants crossed over to have their device programmed to deliver stimulation at a patient-appropriate level. At the one-year time point, participants in the Control/Crossover group have received 8 months of patient-appropriate therapy. | 1 Year | 
| Mean Change in LBP VAS at One Year | Change in LBP VAS at 1 year compared to baseline. The instrument used for evaluating pain is the continuous Visual Analog Scale (VAS) comprised of a horizontal line 10 cm in length, anchored by 2 verbal descriptors, one for each symptom extreme for Low Back Pain. Zero indicates no pain and 10 indicates worst imaginable pain. The value reported is a 7-day average low back pain. After the 120 day visit, participants crossed over to have their device programmed to deliver stimulation at a patient-appropriate level. At the one-year time point, participants in the Control/Crossover group have received 8 months of patient-appropriate therapy. A change to a lower score (negative value) indicates improvement. | 1 Year | 
| Change in Oswestry Disability Index (ODI) at One Year | Change in ODI at 1 year compared to baseline. ODI is reported as a score from 0 to 100%, where 0%-20% indicates minimal disability, 21%-40% indicates moderate disability, 41%-60% indicates severe disability, 61%-80% indicates crippled, and 81%-100% indicates bedbound or an exaggeration of symptoms. After the 120 day visit, participants crossed over to have their device programmed to deliver stimulation at a patient-appropriate level. At the one-year time point, participants in the Control/Crossover group have received 8 months of patient-appropriate therapy. A change to a lower score (negative value) indicates improvement. | 1 Year | 
| Change in European Quality of Life Score on Five Dimensions (EQ-5D) at One Year | Change in EQ-5D at 1 year compared to baseline. The EQ-5D Index is scored on a scale of -0.594 to 1.00, with a score of 1.00 indicating full health. After the 120 day visit, participants crossed over to have their device programmed to deliver stimulation at a patient-appropriate level. At the one-year time point, participants in the Control/Crossover group have received 8 months of patient-appropriate therapy. A change to a higher score (positive value) indicates improvement. | 1 Year | 
| Percent Pain Relief at One Year | PPR is a patient-reported percent of pain relief compared to the pain at baseline, where 0% indicates no pain relief compared to baseline, and 100% indicates complete pain relief compared to baseline. After the 120 day visit, participants crossed over to have their device programmed to deliver stimulation at a patient-appropriate level. At the one-year time point, participants in the Control/Crossover group have received 8 months of patient-appropriate therapy. | 1 Year | 
| Subject Global Impression of Change (SGIC) at One Year | A questionnaire with the following item: Since I enrolled in the study, my overall status is 1) Very much improved, 2) Much improved, 3) Minimally improved, 4) No change, 5) Minimally worse, 6) Much worse, 7) Very much worse After the 120 day visit, participants crossed over to have their device programmed to deliver stimulation at a patient-appropriate level. At the one-year time point, participants in the Control/Crossover group have received 8 months of patient-appropriate therapy. | 1 Year | 
| Resolution of Back Pain at One Year | Resolution of back pain (remitter rate) was defined as a participant with 7-day average low back pain VAS ≤2.5 cm on the 10 cm VAS. After the 120 day visit, participants crossed over to have their device programmed to deliver stimulation at a patient-appropriate level. At the one-year time point, participants in the Control/Crossover group have received 8 months of patient-appropriate therapy. | 1 Year |