Summary of Clinical Trials with Biological Treatment Approaches for Spinal Disease

16 Summary of Clinical Trials with Biological Treatment Approaches for Spinal Disease

Gernot Lang, Ibrahim Hussain, Micaella Zubkov, Yu Moriguchi, Brenton Pennicooke, Rodrigo Navarro-Ramirez, and Roger Härtl

Abstract

Biological-based treatment approaches for cartilaginous and ligamentous parts of the body have laid the foundation for these strategies to be translated to spinal disease. Preclinical reports of different biomolecular, cell-based, and tissue-engineered therapies in animal models have shown promising results, with some of these therapies previously or currently being assessed in human clinical trials.

Although few, these clinical trials have been instrumental in determining how different stages of intervertebral disc (IVD) degeneration correlate with the efficacy of various treatments, as well as which therapies show short-term, but not long-term benefits. This robust topic within the spinal disease research landscape will continue to advance over the coming decades via more comprehensive understanding of the molecular interaction between host tissue, implanted biologics such as stem cells, and anti-inflammatory proteins. Furthermore, as these therapies gain traction, improvements in the surgeon’s ability to deliver treatments safely will also become a major part of future clinical trials. In this chapter, we present an update on completed, aborted, and currently active clinical trials evaluating biological treatment approaches for spinal disease.

Keywords: annulus, biologics, intervertebral disc, nucleus, tissue engineering, regeneration

16.1 Historical Perspective

Current treatment options for degenerative disc disease (DDD), both conservative and surgical, fail to treat the underlying pathology, leading to symptomatlogy and complications. Biological treatment approaches have emerged as a feasible strategy for treating pathological intervertebral disc (IVD) segments without the adverse effects associated with conventional approaches. The aim of biological treatment strategies for DDD is to restore native biomechanics of the IVD and at the same time induce regeneration by promoting anabolism of IVD cells. Early-stage degenerated discs contain a sufficient amount of viable cells to replenish a healthy extracellular matrix (ECM) with assistance from engineered biomolecules, such as recombinant genes or proteins. Mid-stage degenerated discs are characterized by less active cells that are rapidly disappearing, at which point cell-based therapy is the most viable option. When the disc’s structure and function are severely compromised, it has reached terminal-stage degeneration. At this point, it is necessary to replace the degenerated disc with a disclike composite impregnated with autologous tissues or tissues generated in vitro¹^,² (▶ Fig. 16.1).

Fig. 16.1 Summary of biological approaches for intervertebral disc (IVD) repair based on the degree of degeneration.

The concept of using tissue engineering technology to treat musculoskeletal disorders is not new. One of the first biological treatment approaches for DDD was proposed by Wehling et al in 1997, who described using gene therapy to engineer cells with the ability to regenerate ECM components.³ In 2001, Orozco et al were the first to use autologous mesenchymal stem cells (MSCs) harvested from the patients’ bone marrow for injection into the nucleus pulposus (NP) of a degenerated disc. Since then, many similar experiments have been conducted to explore cell therapy techniques to treat DDD, but almost all were pilot studies and contained very small study populations. To date, only a few clinical trials targeting IVD repair or regeneration have been published, and several ongoing clinical trials aimed at disc repair have yet to publish their findings (▶ Table 16.1).

Table 16.1 Published results of clinical trials targeting IVD repair or regeneration

Haufe et al²⁵ 2006
Purpose	To analyze whether hematopoietic precursor stem cells (HSCs) prompt regeneration of disc tissue when injected into degenerated IVDs
Study type	Therapy (intervention), Phase I
Study design	Prospective study
Patient	Discogenic LBP; all patients had attempted endoscopic discectomy to eliminate pain (N =10)
Intervention	Single intradiscal injection of 1 mL of HSCs harvested from patient’s pelvic bone marrow
Comparison	None
Outcome	Follow-up at 6 and 12 mo: VAS
Status/Conclusion	Status: Complete No SAEs. No effect: no patients experienced relief of LBP 80% later underwent surgery
Meisel et al²⁴ 2007
Purpose	To assess the long-term efficacy of autologous disc chondrocyte transplantation (ADCT) in DDD
Study type	Therapy (intervention), Phase I
Study design	Prospective, randomized, multicenter clinical; not blinded (EuroDisc)
Patient	Single-level DDD, Modic 1, failed conservative treatment (N = 28)
Intervention	Discectomy to harvest cells from index IVD, culture of disc cells and transplantation into index IVD 12 weeks following discectomy
Comparison	Discectomy only
Outcome	OPDQ, QBPD, MRI at 3, 6, 12, and 24 months postop; patients’ experiences with surgery
Status/Conclusion	Status: Complete ADCT is a safe procedure ODI + OPDQ are slightly lower in the treatment group No statistical analysis No control group
Yoshikawa et al³⁰ 2010
Purpose	To analyze the regenerative ability of MSCs in degenerated IVDs
Study type	Therapy (intervention), Phase I
Study design	Clinical case report
Patient	DDD, failed conservative treatment (N = 2)
Intervention	Collagen sponge holding MSCs cultured from patient’s bone marrow grafted to degenerated disc; collagen soaked in 10⁵ cells/mL suspension
Comparison	None
Outcome	JOA, VAS, MRI, CT, and X-ray at 6 months and 2 years postop
Status/Conclusion	Status: Complete Low power (n = 2) No SAE Clinical outcome scores improved Morphological outcome questionable (MRI)
Orozco et al³² 2011
Purpose	To assess the feasibility, safety, and efficacy of MSCs for degenerated IVDs
Study type	Therapy (intervention), Phase I
Study design	Prospective pilot study
Patient	DDD and LBP; failed conservative treatment for 6 months (N = 10)
Intervention	Injection of cultured MSCs into NP
Comparison	None
Outcome	MRI, SF-36, VAS, and ODI at 3, 6, and 12 months postop; 85% of improvement occurred within first 3 months
Status/Conclusion	Status: Complete No SAEs No control group Low power Clinical and radiographic outcomes showed improvement 85% of improvement occurred within the first 3 months
Coric et al⁴³ 2013
Purpose	US Investigational New Drug Application (IND) Phase I study to evaluate the safety of cell-based therapy with juvenile chondrocytes for the treatment of lumbar DDD with mechanical LBP
Study type	Therapy (intervention), Phase I
Study design	Prospective, U.S. FDA-regulated IND feasibility trial
Patient	LBP and single-level DDD (Pfirrmann III–IV) without annular rupture; failed = 12 weeks conservative therapy (N = 15)
lntervention	1–2mL intradiscal injection of juvenile chondrocytes (10⁷ cells/mL) with fibrin carrier; cells harvested from articular surface of cadaveric donor tissue
Comparison	None
Outcome	Neurological examinations, serum liver and renal function, ODI, NRS, and SF-36 at 1, 3, 6, and 12 months post-treatment; MRI at 1, 6, and 12 months
Status/Conclusion	Status: Complete Improvements in ODI and NRS No control group Low power No SAE reported
Pettine et al²⁶ 2015
Purpose	To evaluate the use of autologous bone marrow–concentrated cells (BMCs) to treat discogenic LBP in an attempt to avoid or delay lumbar fusion or artificial disc replacement
Study type	Therapy (intervention), Phase I
Study design	Prospective, open-label, nonrandomized, two-arm study, single center
Patient	LBP: ODI ≥ 30, VAS ≥ 40 mm (100-mm scale), height loss <30%, Modic II or less (N = 26)
Intervention	Intradiscal injection of 2–3 mL BMC (single or two adjacent levels), cell concentration varied between patients
Comparison	None
Outcome	ODI, VAS, MRI (Pfirrmann) at 12 months postop; bone marrow concentration analyses
Status/Conclusion	Status: Complete No SAEs Low power No control group Improvement in clinical measures Radiological measures inconclusive
Tuakli-Wosornu et al¹³ 2015
Purpose	To determine whether single injections of PRPs into degenerative IVDs will improve pain and function
Study type	Therapy (intervention), Phase I
Study design	Prospective, double-blind, randomized controlled study
Patient	≥ 6 months LBP, failed conservative treatment, presence of a grade 3 or 4 annular fissure (N = 47)
Intervention	Intradiscal PRP injection (1–2mL); (N = 29)
Comparison	Omnipaque 180, Amersham Health, Princeton, NJ
Outcome	NRS, FRI, physical SF-36, and NASS Outcome Questionnaire at 1, 4 and 8 weeks post-op
Status/Conclusion	Status: Complete Short follow up (2 months) Slight improvement in all clinical scores in experimental group compared to control No SAEs
DePuy Spine⁶^,⁷^,⁸^,⁹ 2016
Purpose	To evaluate safety and preliminary effectiveness of intradiscal rhGDF-5 in patients with early lumbar DDD
Study type	Therapy (intervention), Phase I/II
Study design	Open-label, single administration, dose finding
Patient	Single-level LBP (L3–4 to L5–S1) (L3/L4 to L5/S1) with = 3 months of conservative therapy; ODI of = 30; LBP score = 4 cm (VAS) (N=32)
Intervention	Intradiscal injection of rhGDF-5, 0.25 mg (N=7) and 1.0 mg (N=25)
Comparison	None
Outcome	ODI, VAS, SF-36, neurological assessment
Status/Conclusion	Status: Complete 37.5% of patients were lost to follow-up No statistical analysis Clinical outcomes reveal minimal improvement No effect compared to placebo
Mesoblast Ltd.⁴¹^,⁴² 2016
Purpose	To determine safety of MPCs and carrier injection treatments, and its effectiveness in reducing chronic LBP
Study type	Therapy (intervention), Phase II
Study design	Prospective, double-blind, controlled, multicenter
Patient	Chronic LBP = 6 months, single-level DDD L1-S1, failed 3 months of conservative treatment, ODI = 30, (N = 100)
Intervention	Single intradiscal (NP) injection of MPCs in hyaluronic acid; volumes and concentrations not indicated
Comparison	Sham control: single injection of saline/hyaluronic acid solution
Outcome	VAS and safety evaluation at 1, 3, 6, 12, 24, and 36 months post-injection; MRI at 6, 12, 24, and 36 months post-injection
Status/Conclusion	Ongoing study Results of this study are not yet available on ClinicalTrials.gov (as of time of publication)
Abbreviations: CT, computed tomography; DDD, degenerative disc disease; HSCs, hematopoietic stem cells; IND, investigational new drug; IVD, intervertebral disc; JOA, Japanese Orthopaedic Association; LBP, low back pain; MPCs, mesenchymal precursor cells; MRI, magnetic resonance imaging; MSCs, mesenchymal stem cells; NASS, North American Spine Society; NP, nucleus pulposus; ODI, Oswestry Disability Index; OPDQ, Oswestry Low Back Pain Disability Questionnaire; PRP, platelet rich plasma; QBPD, Quebec Back Pain Disability Scale; rhGDF-5, recombinant human growth and differentiation factor 5; SAE, serious adverse event; VAS, Visual Analog Scale.

Thus, the application of biological treatment strategies for the regeneration of IVDs remains a largely undiscovered field, especially with respect to clinical trials. Much work remains to be done before biomolecular- and cell-based therapies become prevalent treatment options for DDD, such as identifying and characterizing the roles of endogenous IVD stem cells, MSCs, platelet rich plasma (PRP), and cytokine inhibitors (▶ Fig. 16.2).

Fig. 16.2 Generation and application of biological repair strategies for intervertebral disc disease. Abbreviations: AC, autologous chrondrcytes; MSC, mesenchymal stem cell; PRP, platelet rich plasma.

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