E-Poster Orals

EPV030 - DESIGN OF A RANDOMIZED ACTIVE SHAM-CONTROLLED RESTORATIVE NEUROSTIMULATION TRIAL - LEARNINGS FROM THE REACTIV8-B PIVOTAL TRIAL? (ID 318)

Session Name
E-Poster Orals
Presenter
  • G. Baranidharan, United Kingdom
Authors
  • Sam Eldabe, United Kingdom
  • G. Baranidharan, United Kingdom
Presentation Number
EPV030
Presentation Topic
13. Late-Breaking Research

Abstract

Introduction

Clinical trial designs in support of premarket approvals are an inherent compromise between regulatory requirements and practical, robustness and efficiency considerations. ReActiv8-B is an international, multicenter, randomized, parallel arm, active sham-controlled, double-blinded trial with a single-arm cross-over under Investigational Device Exemption, to demonstrate safety and efficacy of a novel restorative neurostimulator aimed at restoring neuromuscular control of the lumbar multifidus muscles in patients with refractory Chronic Low Back Pain (CLBP). We present protocol design features relevant to the interpretation of the detailed trial results which were submitted separately. (clinicaltrials.gov: NCT02577354)

Methods/Materials

We recruited 204 patients with CLBP who after implantation were randomly assigned to receive therapeutic or subthreshold stimulation (sham-control) for 30 minutes, twice daily. The primary endpoint compared responder rates at 120 days, with a ‘Responder’ having ≥30% average VAS reduction without any increase in pain medication. Secondary outcome measures included ODI, EQ-5D, Percent Pain Relief (PPR), Subject Global Impression of Change (SGIC) and Proportion of Remitters (VAS≤2.5cm).

Specific measures to maintain equipoise and blinding of patients, clinicians and assessors included: scripted dialogues; equal visit schedules, treatment instructions and follow-up duration; questionnaire completion before subject interactions; simulated programming; all blinded visits were attended by independent site staff to ensure dialogue neutrality. Blinding effectiveness was assessed at 120 days by direct questioning after which patients in the sham control group crossed over to therapeutic stimulation.

Results

Statistical Analysis

The primary endpoint was tested using a two-sided binomial test for a difference in proportions using multiple imputations. Because dichotomization around a single 30% cut-off inherently leads to a loss of information and statistical power a cumulative rate of responder analysis on the same data was prespecified. Since acute pain conditions unrelated to low back pain and consequent increased analgesics consumption could confound the ITT analysis, a modified-ITT analysis was also prespecified. Secondary endpoints were tested using a completers analysis.

Discussion

We describe the design of the first randomized, active sham-controlled trial of a neurostimulation system for the treatment of CLBP. Treatment effects were known to accrue over time, but the sham response was unknown. Endpoint timing was set to 120 days for ethical and practical considerations. The prospective anticipation of confounding factors and the rigorous trial design, strict blinding and equipoise control measures provide a unique trial design among neuromodulation studies.

Conclusions

Conclusions

The Reactiv8-B trial design followed rigorous quality standards with many unique features.

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