If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Long-Term Outcomes of Restorative Neurostimulation in Patients With Refractory Chronic Low Back Pain Secondary to Multifidus Dysfunction: Two-Year Results of the ReActiv8-B Pivotal Trial
Address correspondence to: Christopher Gilligan, MD, Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 850 Boylston St, Suite 320, Chestnut Hill, MA 02467, USA.
Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital Harvard Medical School, Boston, MA, USA
Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital Harvard Medical School, Boston, MA, USA
Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital Harvard Medical School, Boston, MA, USA
Impaired neuromuscular control and degeneration of the multifidus muscle have been linked to the development of refractory chronic low back pain (CLBP). An implantable restorative-neurostimulator system can override the underlying multifidus inhibition by eliciting episodic, isolated contractions. The ReActiv8-B randomized, active-sham-controlled trial provided effectiveness and safety evidence for this system, and all participants received therapeutic stimulation from four months onward.
Objective
This study aimed to evaluate the two-year effectiveness of this restorative neurostimulator in patients with disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery.
Materials and Methods
Open-label follow-up of 204 participants implanted with a restorative neurostimulation system (ReActiv8, Mainstay Medical, Dublin, Ireland) was performed. Pain intensity (visual analog scale [VAS]), disability (Oswestry disability index [ODI]), quality-of-life (EQ-5D-5L), and opioid intake were assessed at baseline, six months, one year, and two years after activation.
Results
At two years (n = 156), the proportion of participants with ≥50% CLBP relief was 71%, and 65% reported CLBP resolution (VAS ≤ 2.5 cm); 61% had a reduction in ODI of ≥20 points, 76% had improvements of ≥50% in VAS and/or ≥20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 87% of participants had continued device use during the second year for a median of 43% of the maximum duration, and 60% (34 of 57) had voluntarily discontinued (39%) or reduced (21%) opioid intake.
Conclusions
At two years, 76% of participants experienced substantial, clinically meaningful improvements in pain, disability, or both. These results provide evidence of long-term effectiveness and durability of restorative neurostimulation in patients with disabling CLBP, secondary to multifidus muscle dysfunction.
Clinical Trial Registration
The study is registered on clinicaltrials.gov with identifier NCT02577354.
The multifidus muscles are the most important stabilizers of the lumbar spine and play a crucial role in providing segmental stability in response to changes in posture and protection against sudden perturbations.
The isolated muscle contractions required to reverse impaired neuromuscular control are difficult to achieve voluntarily, especially in the presence of underlying inhibition and degeneration of the multifidus muscle.
To overcome these limitations to rehabilitation, a restorative neurostimulation system (ReActiv8, Mainstay Medical, Dublin, Ireland) was developed to electrically stimulate the medial branch of the L2 dorsal ramus nerve to elicit isolated multifidus muscle activation.
New therapy for refractory chronic mechanical low back pain—restorative neurostimulation to activate the lumbar multifidus: one year results of a prospective multicenter clinical trial.
A recent double-blind, randomized, sham-controlled pivotal trial provided safety and effectiveness evidence for premarket approval from the United States Food and Drug Administration (FDA) in 2020.
The objective of the prospective, observational analyses reported here was to evaluate the two-year effectiveness of this restorative neurostimulator in patients with disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery.
Materials and Methods
Data for this secondary analysis were obtained from the cohort of 204 patients enrolled at 26 multidisciplinary centers in the United States, Australia, and Europe in the randomized, sham-controlled, double-blind pivotal trial. All patients were receiving therapeutic stimulation from four months onward. Details regarding patient eligibility, study design, implant procedure, and medium-term results through one year have been previously published.
Study participants were adults with a diagnosis of disabling mechanical CLBP (ie, a seven-day recall of average LBP of ≥6.0 and ≤9.0 cm on the 10-cm visual analog scale [VAS] and Oswestry disability index [ODI] of ≥21 and ≤60 points on a scale from 0 to 100). Mechanical CLBP was defined as low back pain without significant radicular symptoms. Participants had low back pain on at least half of the days in the previous year, were nonresponsive to a minimum of 90 days of nonsurgical medical management including medication and physical therapy, and had a positive prone instability test result (provocative pain test using posterior-anterior pressure on individual lumbar vertebrae that improves with activation of the posterior lumbar musculature) consistent with impaired neuromuscular control of the multifidus muscle and consequent lumbar segmental instability.
The conduct of the trial complied with the FDA regulations, ISO 14155, International Conference on Harmonization, and the Declaration of Helsinki. Local institutional review board or ethics committee approval was obtained at each site, and all participants provided written informed consent. Results are reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines.
The study is registered on clinicaltrials.gov with identifier NCT02577354.
Procedures
All participants received the implanted restorative neurostimulation system (Fig. 1).
Figure 1Implantation procedure and materials. Stimulation leads were placed bilaterally near the L2 medial branch of the dorsal ramus nerve as it crosses the L3 transverse process and distally fixated to the L2/3 intertransversarii using flexible tines. The proximal sections were tunneled subcutaneously to the surgically created pocket in the gluteal or lower lumbar region where they were connected directly to the implantable pulse generator.
During the open-label phase of the trial, all devices were programmed to deliver therapeutic stimulation at a frequency of 20 Hz, a pulse width of 214 μsec, and participant-specific pulse amplitudes and electrode configurations to elicit tonic multifidus contractions for 10 seconds twice per minute. All participants were instructed and trained to deliver two 30-minute stimulation sessions per day while prone or lying on their side using their wireless activator.
Outcomes
Prespecified outcome measures included the seven-day recall of average low back pain on the 10-cm VAS,
and medication usage. These outcomes were assessed and compared with baseline at six months and one and two years, and annual follow-ups are scheduled for a total of five years.
Ongoing safety reporting included serious device- or procedure-related adverse events (AEs) that were actively solicited and documented at each visit and reported and coded according to the Medical Dictionary for Regulatory Activities, version 19.1. The Clinical Events Committee (CEC) adjudicated all AEs.
Data Analysis
Descriptive statistics including mean and standard deviation or standard error of the mean, 95% confidence intervals (CIs), median, first and third quartiles (Q1 and Q3) were used to summarize continuous variables. Binary outcomes were represented as counts and proportions.
To reduce potential bias caused by incomplete follow-up, imputation for missing data was stratified based on the reason for missingness. Baseline observation carried forward, or “failure” for binary outcomes, was used for participants withdrawn for reported lack of efficacy at any time or for permanent explant after infection. For those withdrawn for other reasons (ie, precautionary device removal for magnetic resonance imaging [MRI], resolution of pain, a relocation, or otherwise lost to follow-up) or random missed visits, the mixed-effects model repeated measures (MMRM) approach was used to provide implicit imputations of missing data for continuous outcomes.
To evaluate mean changes from baseline, 95% CIs and adjusted paired t-tests derived from MMRM contrasts were used. Two-sided p values less than 0.05 were considered statistically significant.
To estimate the proportion of patients achieving “success” for the defined binary outcome variables, multiple imputation (MI) was used for overall estimates of success by visit with associated 95% confidence limits.
Analyses were performed using SAS version 9.3 (SAS Institute Inc, Cary, NC).
Results
Study Population
The demographic and baseline characteristics of the 204 participants are summarized in Table 1. Participants had a mean age of 47 ± 9 years, and 54% were women. The mean duration of CLBP was 14 ± 11 years (range from 7 months to 50 years) from the onset of the first occurrence, and the mean percentage of days with LBP in the previous year was 97 ± 8%. The mean VAS was 7.3 ± 0.7 cm, the mean ODI was 39 ± 10, and the mean EQ-5D-5L index was 0.585 ± 0.174. All participants had undergone physical therapy with an average of 31 ± 52 sessions. Of all participants, 12% had undergone medial branch rhizotomy (>1 year before enrollment), 49% had received spinal injections (>30 days before enrollment), and 37% were taking opioid analgesics for LBP.
Table 1Baseline Characteristics of the Study Population at Baseline.
Characteristic
Participants Combined group (N = 204) Mean ± SD or n/N (%)
Scores on the European Quality of Life with five dimensions and five levels (EQ-5D-5L) index range from −0.5 to 1, with higher scores indicating better quality of life.
0.585 ± 0.174
∗ The BMI is the weight in kilograms divided by the square of the height in meters.
† Scores on the VAS for average recall low back pain over the past seven days range from 0 to 10, with higher scores indicating more severe pain.
‡ Scores on the ODI range from 0 to 100, with higher scores indicating more severe disability.
§ Scores on the European Quality of Life with five dimensions and five levels (EQ-5D-5L) index range from −0.5 to 1, with higher scores indicating better quality of life.
Longitudinal follow-up data were available for 190 of 204 participants (93%) at six months, 176 of 204 (86%) at one year, and 156 of 204 (79%) at two years (Fig. 2).
Figure 2CONSORT flow diagram for participant disposition.
At the two-year follow-up, ten participants had missed their follow-up visit, and 38 participants had been withdrawn from the study after permanent system explant (31) or otherwise lost to follow-up (7). One participant in whom the system was explanted for infection was reimplanted after the infection had cleared (Fig. 2).
Two-Year Outcomes
Completed-Cases Analysis (n = 156)
Key efficacy outcomes progressively improved over time, and changes from baseline were statistically significant and clinically meaningful at all follow-ups (p < 0.0001; Figs. 3 and 4, Table 2).
Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society.
By two years, the mean average LBP VAS had improved by −4.8 ± 0.2 cm (95% CI −5.2 to −4.5; p < 0.0001), and 72% of participants had a ≥50% reduction in VAS, with an average reduction of 85%, 62% of participants had a ≥70% VAS reduction, and 67% had resolution of CLBP (VAS ≤ 2.5 cm), with an average residual VAS of 0.97 cm. The mean ODI score decreased by −21.4 ± 1.3 (95% CI −24.0 to −18.7; p < 0.0001), and 62% of participants had a ≥20-point ODI reduction, with an average reduction of 32 points. The mean EQ-5D-5L index improved by 0.218 ± 0.017 (95% CI 0.184 to 0.253; p < 0.0001). The proportion of participants with a reduction in LBP VAS of ≥50% and/or ODI of ≥20 points without an increase in either was 77%. The proportion who exceeded these cut-offs in both VAS and ODI was 57%. Within the cohort of participants with two-year follow-up data, 57 of 156 (37%) were taking opioid analgesics at baseline, 34 of 57 (60%) had voluntarily discontinued (39%) or reduced (21%) opioid use, and 1 of 57 (2%) had increased dosage.
Figure 3Mean ratings over time for a. low back pain VAS, b. Oswestry disability index, and c. EQ-5D-5L index. All changes from baseline p < 0.0001. Error bars represent the standard error of the mean.
Figure 4Response rates at common clinical importance thresholds for a. VAS (reduction ≥50% and 70%, and absolute VAS ≤ 2.5 cm), and b. ODI (≥20 points) and composites of VAS and ODI (≥50% and/or 20 points, ≥50% and/or 20 points). Solid lines represent completed cases, and dashed lines represent imputation for missing data (N = 204).
For continuous outcomes p < 0.0001 for two-sided t-test if change from baseline differs from 0.
N = 204
N = 190
N = 204
N = 176
N = 204
N = 156
N = 204
LBP VAS (cm)
7.3 ± 0.7
3.7 (0.2)
3.9 (0.2)
3.0 (0.2)
3.4 (0.2)
2.4 (0.2)
3.1 (0.2)
Change in VAS (cm)
−3.6 (0.2) (−3.9, −3.3)
−3.4 (0.2) (−3.8, −3.1)
−4.3 (0.2) (−4.7, −3.9)
−3.9 (0.2) (−4.3, −3.6)
−4.8 (0.2) (−5.2, −4.5)
−4.2 (0.2) (−4.6, −3.8)
Change in VAS (%)
−48.6 (2.7) (−53.9, −43.3)
−47.1 (2.6) (−52.3, −41.9)
−58.9 (2.6) (−64.1, −53.6)
−54.3 (2.7) (−59.5, −49.0)
−66.7 (2.6) (−71.7, −61.6)
−58.1 (2.7) (−63.4, −52.8)
≥30% improvement in VAS
66.1 (125/189) (59.4, 72.9)
63.2 (3.5) (56.5, 70.0)
73.9 (130/176) (67.4, 80.4)
66.9 (3.4) (60.3, 73.6)
82.6 (128/155) (76.6, 88.6)
71.6 (3.3) (65.1, 78.1)
≥50% improvement in VAS
52.9 (100/189) (45.8, 60.0)
51.0 (3.6) (44.0, 58.0)
63.6 (112/176) (56.5, 70.7)
58.0 (3.5) (51.1, 65.0)
71.6 (111/155) (64.5, 78.7)
62.1 (3.5) (55.1, 69.0)
≥70% improvement in VAS
33.9 (64/189) (27.1, 40.6)
33.2 (3.4) (26.5, 39.9)
46.6 (82/176) (39.2, 54.0)
43.0 (3.6) (36.1, 50.0)
61.9 (96/155) (54.3, 69.6)
54.3 (3.7) (47.1, 61.5)
LBP resolution (VAS ≤ 2.5 cm)
39.2 (74/189) (32.2, 46.1)
38.3 (3.5) (31.4, 45.1)
51.7 (91/176) (44.3, 59.1)
47.7 (3.5) (40.7, 54.6)
66.5 (103/155) (59.0, 73.9)
57.6 (3.6) (50.5, 64.7)
ODI
39.1 ± 10.3
21.9 (1.1)
22.7 (1.0)
19.0 (1.4)
20.7 (1.0)
17.6 (1.2)
20.2 (1.0)
Change in ODI
−17.0 (1.1) (−19.2, −14.8)
−16.4 (1.0) (−18.4, −14.4)
−19.9 (1.2) (−22.3, −17.6)
−18.4 (1.0) (−20.4, −16.4)
−21.4 (1.3) (−24.0, −18.7)
−18.9 (1.0) (−21.0, −16.8)
Change in ODI (%)
−43.0 (2.8) (−48.5, −37.4)
−41.5 (2.7) (−46.8, −36.1)
−50.5 (2.9) (−56.3, −44.8)
−46.4 (2.8) (−51.8, −41.0)
−54.3 (3.2) (−60.6, −48.0)
−47.5 (2.8) (−53.0, −42.0)
≥20-point improvement in ODI
48.1 (91/189) (41.0, 55.3)
46.7 (3.5) (39.8, 53.7)
57.4 (101/176) (50.1, 64.7)
53.4 (3.5) (46.5, 60.3)
61.3 (95/155) (53.6, 69.0)
54.8 (3.6) (47.7, 61.9)
Composite of VAS and ODI
≥50% improvement in VAS and/or ≥20 points ODI
63.5 (120/189) (56.6, 70.4)
60.4 (3.5) (53.6, 67.2)
73.3 (129/176) (66.8, 79.8)
67.4 (3.4) (60.8, 74.0)
77.3 (119/154) (70.7, 83.9)
67.4 (3.5) (60.4, 74.3)
≥50% improvement in VAS and ≥20 points ODI
37.8 (71/188) (30.8, 44.7)
36.8 (3.4) (30.0, 43.5)
47.7 (84/176) (40.3, 55.1)
44.0 (3.6) (37.0, 51.1)
56.5 (87/154) (48.7, 64.3)
49.9 (3.6) (42.8, 57.1)
EQ-5D-5L index
0.585 ± 0.174
0.765 (0.010)
0.758 (0.011)
0.780 (0.012)
0.762 (0.011)
0.798 (0.013)
0.768 (0.011)
Change in EQ-5D-5L index
0.180 (0.014) (0.153, 0.207)
0.173 (0.011) (0.151, 0.194)
0.198 (0.016) (0.167, 0.229)
0.177 (0.011) (0.156, 0.199)
0.218 (0.017) (0.184, 0.253)
0.183 (0.011) (0.161, 0.205)
PPR (%)
55.0 (2.5) (50.1, 59.9)
53.3 (2.5) (48.4, 58.2)
65.7 (2.4) (60.9, 70.5)
60.7 (2.5) (55.8, 65.6)
72.1 (2.4) (67.3, 77.0)
62.3 (2.5) (57.3, 67.3)
SGIC “Better” or “Much better”
57.4 (109/190) (50.3, 64.4)
55.1 (3.5) (48.2, 62.0)
71.6 (126/176) (64.9, 78.3)
65.9 (3.4) (59.3, 72.5)
78.6 (121/154) (72.1, 85.1)
68.6 (3.4) (61.9, 75.2)
TSQ “Definitely satisfied”
64.7 (123/190) (57.9, 71.5)
62.8 (3.4) (56.0, 69.5)
78.2 (136/174) (72.0, 84.3)
71.8 (3.2) (65.5, 78.1)
80.0 (124/155) (73.7, 86.3)
68.3 (3.4) (61.6, 75.1)
CGI “Much better”
56.8 (108/190) (49.8, 63.9)
55.0 (3.6) (48.0, 62.0)
73.3 (129/176) (66.8, 79.8)
67.5 (3.4) (60.8, 74.1)
77.6 (118/152) (71.7, 84.3)
66.6 (3.6) (59.6, 73.7)
Continuous outcome estimates from mixed model repeated measures regression models adjusted for baseline, all other binary outcomes analyzed with MI for missing data. Statistics are expressed as % (n/N) for binary outcomes and N, mean (standard error) for continuous outcomes.
∗ For continuous outcomes p < 0.0001 for two-sided t-test if change from baseline differs from 0.
A side-by-side comparison of the completed-cases analysis (n = 156) and the imputed intention-to-treat (ITT) analysis (N = 204) is provided in Table 2. Reported outcomes remained statistically significant (p < 0.0001) and clinically meaningful at all follow-ups.
Device Use
Over 94% of participants continued delivering treatment between one and two years. During the 60 days leading to the six-month follow-up, the median device use was 88% (Q1 73%, Q3 96%) of the maximum duration possible (number of days times the maximum duration of 60 minutes daily); for the 90 days leading to the 12-month follow-up, it was 77% (Q1 48%, Q3 90%); and for the 90 days leading to the 24-month follow-up, it was 42% (Q1 6.5%, Q3 75%) (Fig. 5).
Figure 5Interquartile ranges of device use as a percentage of the maximum cumulative duration permitted.
Device- or procedure-related serious AEs (SAEs) are summarized in Table 3 by follow-up interval. Events through the one-year visit have been discussed previously.
No additional device- or procedure-related SAEs were reported, and no lead migrations were observed. Overall, 45 of 204 participants (22%) underwent a total of 47 surgical interventions, during which 32 systems were removed (16%), one system was reimplanted (<1%), four pulse generators were repositioned (2%), and ten participants had their leads replaced (5%). Reasons for system removal were lack of efficacy (n = 18), infection (n = 6), safety precaution before MRI scan (n = 6), resolution of LBP (n = 1), and relocation to a remote area without device follow-up infrastructure (n = 1). Seven unrelated SAEs were reported for seven participants (3%) during the first year, and six unrelated SAEs were reported for six participants (3%) during the second year of the follow-up. All 13 events were reviewed by the CEC and adjudicated as unrelated to the device or procedure.
Table 3Device- and Procedure-Related SAEs and Surgical Interventions.
Restorative neurostimulation is indicated for patients with refractory mechanical CLBP secondary to multifidus muscle dysfunction and no pathology seen on MRI that is clearly identified and is likely the cause of the CLBP that is amenable to surgery.
Before enrollment, all participants had failed conventional medical management, which included at least physical therapy and medication for LBP. Most participants had undergone one or more interventional procedures, and over a third were on chronic opioids. Published studies on this condition consistently report that these patients very rarely experience spontaneous, substantial improvements in their pain and disability.
Longitudinal follow-ups demonstrated a progressive recovery trajectory that is consistent with restoration of multifidus neuromuscular control. At the two-year follow-up, durable and clinically substantial benefits had accrued in all predefined outcome measures (p < 0.0001). Although the study did not directly compare restorative neurostimulation with other available therapies, the improvements were more substantial than those seen with other available therapies for this patient population, such as motor control exercises.
At baseline, average pain was severe (VAS of 7.3 cm) and disability marginally severe (ODI of 39.1), but after two years of treatment, average pain and disability were mild (2.4 cm and 17.6, respectively). Individual clinical benefits were reflected in the “responder” analysis of the core outcome domains, in which 72% of participants showed a substantial (≥50%) pain reduction,
with an average improvement from baseline within this cohort of 84%. A total of 67% of participants reported LBP resolution with an average residual VAS of 0.97 cm, and 61% of participants reported a substantial (≥20 points) ODI improvement,
Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society.
Food and Drug Administration. Guidance for Industry on Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims; 2009.
A total of 77% of participants experienced a substantial improvement in LBP VAS (≥50%) and/or ODI (≥20 points), and 57% experienced such substantial improvements in both. The average EQ-5D-5L utility score had increased from 0.585 to 0.798, which closely approaches the age-matched US population norm of 0.815.
Insufficient relief from existing treatments commonly leads to prescription of chronic opioid therapy for patients with CLBP, despite frequent poor outcomes.
Even though participants were considered refractory to pain medication, 76 of 204 (37%) were receiving chronic opioid therapy for their CLBP at baseline. Of the 57 of 156 participants who used opioids at baseline and had a two-year follow-up, 60% had either voluntarily discontinued use or decreased consumption, and only one patient had increased intake. These results suggest that the treatment helps patients voluntarily abandon or reduce opioid consumption. Similar reductions were reported for other LBP medications, including nonsteroidal anti-inflammatory drugs (NSAIDs), simple analgesics, and muscle relaxants, providing further support of clinical benefit.
Device Use
Device use remained high during the second year, with over 94% of participants delivering treatment. Among the 103 of 155 participants (67%) with resolution of CLBP, median device use was 48% (Q1 15%, Q3 74%), which was not materially different from the overall distribution. Eight participants did not administer any treatment during the second year, and four of them had resolution of LBP with a residual average VAS of 1.4 cm. A total of 16 participants had administered over 90% of the maximum permitted treatment amount, and 13 also had resolution of LBP with a residual average VAS of 0.42 cm. This illustrates that even though LBP resolution can be sustained in the absence of stimulation, participants may prefer to continue with therapy delivery despite resolution of their symptoms. Within the remission cohort, three participant profiles are thus emerging: those who stop or minimize stimulation and remain in remission, those who require occasional stimulation to remain in remission or to manage flare-ups, and those who regularly administer a high level of stimulation despite being in remission.
Safety
The overall incidence of related SAEs was 8 of 204 (3.9%; Table 3), including six post-surgery infections requiring system removal, all reported during the first four months of follow-up. The permanent system removal rate of 31 of 204 (15.2%) is in line with spinal cord stimulation reports over the same two-year period,
and the rate of participants requiring surgical intervention, 45 of 204 (20%), is comparable with published incidence data for other neuromodulation therapies for chronic pain.
Treatment-limiting complications of percutaneous spinal cord stimulator implants: a review of eight years of experience from an academic center database.
Treatment-limiting complications of percutaneous spinal cord stimulator implants: a review of eight years of experience from an academic center database.
The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee.
No lead migrations were observed in this trial, demonstrating the effectiveness of the distal fixation tines.
Strengths and Limitations
The strength of this study is that it reports on a relatively large and homogeneous cohort of patients with severe and refractory CLBP with an extended follow-up duration of two years. The study demonstrates durable benefits in patients with a baseline pain duration longer than one year. However, because only three patients had a pain duration between 6 and 12 months, the benefits of earlier intervention remain to be studied.
The main limitation is the absence of a long-term comparator because of therapy activation in the sham-control group after conclusion of the blinded phase at four months. Furthermore, studies with long follow-up durations will inherently have to account for missing data, particularly those for chronic pain conditions.
Permutt TJ. E9(R1)Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials. Food and Drug Administration, HHS. 2017:50433–50434.
To inform the interpretation of the complete-cases analyses (n = 156), we have provided supporting ITT analyses (N = 204) using transparent and conservative MMRM imputation, which was stratified based on likely randomness of, and reason for, missing data. The relatively small difference across all outcome measures between the completed-cases and imputed analyses and the statistical significance and clinical relevance of results in both (Table 2) instills confidence in the robustness of our data and the validity of the conclusions drawn.
Conclusions
The two-year results of the ReActiv8-B trial show durable, statistically significant, and clinically substantial benefits in a cohort of patients with severe, disabling CLBP and multifidus muscle dysfunction who were refractory to conservative care including physical therapy and medications. Participants demonstrated improvements in pain and disability that increased the longer they were treated. This recovery trajectory is consistent with restoration of neuromuscular control and structural muscle changes. The safety profile of the therapy was favorable compared with that of available implantable neurostimulators for the treatment of back pain.
Acknowledgements
The authors thank the subinvestigators, research coordinators, and nursing staff at the study sites for their contribution to site management and patient care. The authors thank Robert H. Dworkin, PhD, for his advice on interpretation and presentation of trial results, Teresa Yurik, MS, and Lisa Grant, MS, for their statistical advice and data analysis support, and Diane Burnside, BS, and Jason Shiroff, BS (Mainstay Medical Clinical Department), for management of the trial.
Authorship Statements
Christopher Gilligan, Richard Rauck, James Rathmell, Timothy Deer, Shivanand Lad, Jeffrey Fischgrund, Bruce Mitchell, Kristiaan Deckers, Kris De Smedt, Sam Eldabe, Marc Russo, Jean-Pierre Van Buyten, Ganesan Baranidharan, and Vivek Mehta contributed to the development of the protocol. Christopher Gilligan drafted the manuscript, and Sam Eldabe revised the manuscript. All authors reviewed and approved the manuscript before initial submission. All authors were clinical investigators on the trial, with the following exceptions: Richard Rauck served as chair of the Data Monitoring Committee, James Rathmell served as chair of the Clinical Events Committee, William Klemme served as independent MRI reviewer, and Jan Pieter Heemels provided editorial support.
New therapy for refractory chronic mechanical low back pain—restorative neurostimulation to activate the lumbar multifidus: one year results of a prospective multicenter clinical trial.
Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society.
Food and Drug Administration. Guidance for Industry on Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims; 2009.
Treatment-limiting complications of percutaneous spinal cord stimulator implants: a review of eight years of experience from an academic center database.
The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee.
Permutt TJ. E9(R1)Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials. Food and Drug Administration, HHS. 2017:50433–50434.
Source(s) of financial support: This study was funded by Mainstay Medical.
Conflicts of Interest: Mainstay Medical (“Mainstay”) funded this pivotal regulatory trial and compensated all investigators and committee members either directly (personal fees) or indirectly (payments to institution). Travel expenses related to investigator meetings and training were reimbursed only with prior authorization.
Disclosures outside the submitted work: C. Gilligan reports payment of part of his salary to his department and stock-options received from Mainstay, personal fees from Medtronic, Saluda, Abbott, Persica, Eli Lilly, Iliad, research funded by Sollis, and expert witness testimony fees; W. Vollschenk reports personal fees from Mainstay; M. Russo reports personal fees from Mainstay; C. Gilmore reports personal fees and other from SPR, and personal fees from Nevro, Nalu, Biotronik, Boston Scientific, and Saluda; V. Mehta reports grants from Mainstay and Abbott, grants and personal fees from Boston Scientific and Medtronic; K. De Smedt reports personal fees from Mainstay; U. Latif reports personal fees from Medtronic; P. Georgius reports personal fees from Boston Scientific, Abbott and Spectrum; J. Gentile reports personal fees from Mainstay; B. Mitchell reports personal fees from Mainstay; M. Langhorst reports personal fees from Mainstay and Vivex; F. Huygen reports grants and personal fees from Abbott and Saluda, and nonfinancial support from Boston Scientific; G. Baranidharan reports a grant from Mainstay, grants and personal fees from Nevro, Abbott, Boston Scientific, and personal fees from Nalu and Stryker; V. Patel reports personal fees from Mainstay, grants from Orthofix, Pfizer, Premia Spine, Medicrea, Globus, Aesculap, and 3-Spine; A. Gulve reports personal fees from Medtronic and Boston Scientific, grants and personal fees from Nevro and Abbott; J.P. Van Buyten reports personal fees from Mainstay, and grants and personal fees from Medtronic, Nevro, Boston Scientific and Abbott; A. Tohmeh reports stock ownership and personal fees with two spine companies; J. Fishgrund reports personal fees from Stryker, Relievant, FzioMed, BioVentus and Asahi Kasei; F. Ahadian reports a grant from Mainstay; T. Deer reports grants, personal fees, and other from Abbott, Saluda and SPR, grants and personal fees from Boston Scientific, personal fees and other from SpineThera, Nalu, Cornerloc and Ethos, personal fees from Stimgenics, Flowonix and SI Bone, and a patent pending with Abbott; J. Rathmell reports personal fees from the American Board of Anesthesiology, and personal fees from the American Society of Anesthesiology; G. Maislin reports personal fees from Mainstay. J.P. Heemels reports personal fees and equity interests with Mainstay; S. Eldabe reports personal fees and non-financial support from Mainstay, grants and personal fees from Medtronic, and other from Abbott.
The remaining authors have no conflicts of interest to disclose outside of the submitted work.
06386-8&id=gr1.jpg){kind=link}
06386-8&id=gr2.jpg){kind=link}
06386-8&id=gr3.jpg){kind=link}
06386-8&id=gr4.jpg){kind=link}
06386-8&id=gr5.jpg){kind=link}