Safety and Efficacy of Novel Epidural Clonidine Micropellets for Lumbosacral Radiculopathy

Abstract

Background: Chronic low back and leg pain is a leading cause of disability driving significant health care expenditure and lost productivity. Treatment options such as physical therapy, corticosteroids epidural injections (ESI) or spine surgery have limited long term effectiveness, are costly, and may cause significant morbidity. Clonidine has well-known anti-neuropathic pain (analgesic) with anti-inflammatory properties. A novel, targeted-delivery formulation of slow-release biodegradable polymer (Poly (D, L-lactide) clonidine has the ability to deliver sustained, high clonidine levels in tissues to provide prolonged pain relief while minimizing systemic exposure and side effects. Methods: A pilot multicenter study was performed to investigate safety, pharmacokinetics (PK) and activity of clonidine micropellets in patients with chronic lumbosacral radiculopathy. Three sequential cohorts of 18 subjects each received a single epidural injection of clonidine 0.325 mg, 0.975 mg or 1.95 mg (1, 3 or 6 micropellets, respectively) at the interlaminar epidural level that corresponds to the painful dermatomes. Clonidine PK was evaluated at multiple time points for 84 days. Paired t-tests were performed to examine changes from baseline within each cohort, and analysis of covariance evaluated differences between dose levels. Numeric Rating Scale (NRS) and Roland Morris Disability Scale (RMS-Q) were recorded at baseline and followed up to one year postinjection. Results: The peak plasma clonidine concentration was observed 24 hours following the injection in each cohort. The mean elimination half-life ranged from 13 to 20 days. There was a statistically significant reduction in leg pain from baseline at all time points up to 1 year, in all cohorts with similar improvement in each group. All cohorts showed statistically significant improvement in the RMS-Q at all timepoints. Adverse events and rescue medications were also recorded. Conclusion: Results of this trial support the hypothesis that Clonidine Micropellets would safely and slowly deliver clonidine over a prolonged period. Clonidine’s anti-neuropathic and anti-inflammatory effects could treat the radicular pain process at the nerve root resulting in long term pain relief. Trial Registration: ClinicalTrials.gov (NCT01917825). Funding Statement: Phase II trial was funded by Medtronic Inc. Declaration of Interests: Nagy A. Mekhail: Consultant: Boston Scientific, Sollis Therapeutics, and Relievant Medsystems, Inc. Receiving research support from Mallinckrodt, Mesoblast, Halyard, and Neuros Medical Independent medical monitor for Closed-loop SCS “Evoke study” sponsored by Saluda Medical Pty. Ltd., HF10 for PDN “Senza-PDN study” sponsored by Nevro Corp. and Mild for LSS “Motion study” sponsored by Vertos Medical. Ali R. Rezai: Equity position: Sollis Therapeutics and Neurotechnology Innovation Management Board of Directors: Sollis Therapeutics Pragya B. Gupta: Nothing to disclose W Porter McRoberts: Consultant: Nalu, Abbott, Bioness, Sollis, BGT Shareholder of Nalu Gregory J. Fiore: Consultant to Sollis Therapeutics Bryan A. Jones: Employee of Sollis Therapeutics Lou-Anne G. Acevedo-Moreno: Nothing to disclose Chris J. Gilligan: Funded Research: Sollis Therapeutics, Mainstay Medical Consulting: Medtronic, Abbott, Saluda, Nuvectra Ramsin M. Benyamin: Consultant: Medtronic, Avanos, Vertiflex Ethics Approval Statement: This study was approved by the institutional review boards at 6 participating sites. The study was conducted in compliance with the Declaration of Helsinki principles for human medical research, and the principles of good clinical practice and data management. Written informed consent was obtained from all study participants.