Placebo-controlled Study to Evaluate Rexlemestrocel-L Alone or Combined With Hyaluronic Acid in Participants With Chronic Low Back Pain

Study Overview
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Brief Summary
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This is a prospective, multicenter, randomized, double-blind, placebo-controlled Phase 3 study designed to evaluate the safety and efficacy of Mesoblast's rexlemestrocel-L alone or combined with hyaluronic acid (HA) in participants with chronic low back pain (> 6 months) associated with moderate radiographic degenerative changes of a disc.

Official Title
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A Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of a Single Injection of Rexlemestrocel-L Alone or Combined With Hyaluronic Acid (HA) in Subjects With Chronic Low Back Pain

Conditions
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Degenerative Disc Disease

Intervention / Treatment
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* Drug: Rexlemestrocel-L
* Drug: Rexlemestrocel-L + HA Mixture
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants 18 years of age and older If female of childbearing potential, participant is non-pregnant, non-nursing, and agrees to use highly effective methods of contraception for a minimum of 24 months post-treatment Signed informed consent and country-appropriate privacy forms indicating participant is willing to undergo treatment and willing to be available for each examination scheduled over the study duration Have documented diagnosis of moderate radiographic degeneration of an intervertebral disc from L1 to S1, with a disc suspected of causing chronic low back pain (CLBP) associated with moderate radiographic degeneration at a lumbar disc is defined as the following (participant must meet all of the listed conditions): Chronic low back pain for at least 6 months Have failed 6 months of conservative back pain care. (Conservative treatment regimens may include any or all of the following: initial rest, medications [e.g., anti-inflammatory, analgesics, narcotics/opioids, muscle relaxants], massage, acupuncture, chiropractic manipulations, activity modification, home-directed lumbar exercise program, and non-invasive pain control treatments or procedures) Have at a minimum undergone supervised physical therapy, such as daily walking routines, therapeutic exercises, and back education programs specifically for the treatment of low back pain and taken a pain medication for back pain (e.g. non-steroidal anti-inflammatory drug (NSAID) and/or opioid medication). Change from normal disc morphology of the index disc as defined by radiographic evaluation by the core imaging evaluation provider. Radiographs must show all of the following: A modified Pfirrmann score of 3, 4, 5 or 6 on magnetic resonance imaging (MRI) at the index disc Modic Grade II changes or less on MRI at the index disc With or without contained disc protrusion at the index disc on MRI e. Low back pain of at least 40mm and not more than 90mm of 100mm on low back pain visual analogue scale (VAS) (average pain over 24 hours) f. Leg pain ≤20mm in both legs on a 100mm VAS scale g. Oswestry disability index (ODI) score of at least 30 and no more than 90 on a 100 point scale. Exclusion Criteria: Female participants who are pregnant or nursing, or women planning to become pregnant in the first 24 months post-treatment Extreme obesity, as defined by National Institutes of Health (NIH) Clinical Guidelines Body Mass Index (BMI > 40) Have undergone a surgical procedure (e.g. discectomy, intradiscal electrothermal therapy, intradiscal radiofrequency, artificial disc replacement, interbody fusion) on the disc at the index or adjacent level Osteoporosis, as defined by dual-energy X-ray absorptiometry (DEXA) scan. A DEXA T-score of ≤ -2.5 will exclude the participant. Any lumbar intradiscal injection, including steroids, into the index or adjacent discs prior to treatment injection, with the exception of the following injections performed at least 2 weeks prior to study treatment: Contrast medium (discography or other diagnostic injection) NSAIDs Nerve-blocking anesthetics (e.g., lidocaine, bupivacaine) Antibiotics Saline Have undergone a procedure affecting the structure/biomechanics of the index disc level (e.g., posterolateral fusion) Active malignancy or tumor as source of symptoms or history of malignancy within the 5 years prior to enrolment on study Have been a recipient of prior allogeneic stem cell/progenitor cell therapy for any indication or autologous stem cell/progenitor cell therapy or other biological intervention to repair the index intervertebral disc An average baseline morphine equivalent dose (MED) of >75mg/day as determined by e-diary entries during the screening period Taking systemic immunosuppressants A medical condition, serious intercurrent illness, or extenuating circumstance that would preclude participation in the study or potentially decrease survival or interfere with ambulation or rehabilitation. Participants involved in spinal litigation, including workman's compensation, unless litigation is complete Are transient or has a severe alcohol or substance abuse problem Clinically significant nerve pain (e.g., chronic radiculopathy or neuropathy) Clinically significant sacroiliac joint pain Compressive pathology due to stenosis or disc protrusion on MRI with associated clinical symptoms defined as leg pain VAS>20mm out of 100mm or neurologic deficit on neurologic exam Disc extrusion with a maximum dimension greater or equal to twice the posterior height of the disc, or disc sequestration in the lumbar spine on MRI as determined by radiographic core lab Modified Pfirrmann score of 7 or 8 at any lumbar level (L1-S1) on MRI evaluation as determined by radiographic core lab Symptomatic involvement of more than one lumbar disc Symptomatic central vertebral canal stenosis as defined by neurogenic claudication Spondylolisthesis or retrolisthesis Grade 2 and above or Spondylolysis at the index or adjacent level(s) Lumbar spondylitis or other undifferentiated spondyloarthropathy affecting the index disc Spinal deformity defined as lumbar scoliosis with a Cobb angle of the lumbar spine greater than 15 degrees Any fracture of the spine at the index or adjacent levels that has not healed, or clinically compromised vertebral bodies at the index level due to current or past trauma Facet pain at the index level or adjacent segments as determined by a diagnostic medial branch block (a facet block injection is not acceptable for making this determination) to rule out facet joint involvement. Full thickness annular tears in the index level as determined by free flowing contrast media through the annulus fibrosis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rexlemestrocel-L<br>Participants received rexlemestrocel-L 2.0 mL injection of approximately 6 million rexlemestrocel-L cells in freeze media mixed in a 1:1 by-volume ratio with saline on Day 0 (Visit 2). | Drug: Rexlemestrocel-L<br>* Rexlemestrocel-L injection<br>|
| Experimental: Rexlemestrocel-L + HA<br>Participants received rexlemestrocel-L 2.0 mL injection of approximately 6 million rexlemestrocel-L cells in freeze media mixed in a 1:1 by-volume ratio with hyaluronic acid (HA) solution on Day 0 (Visit 2). | Drug: Rexlemestrocel-L + HA Mixture<br>* Rexlemestrocel-L was combined in 1:1 by-volume ratio with HA solution and the resulting mixture was injected<br>|
| Placebo Comparator: Placebo<br>Participants received saline solution as matching-placebo on Day 0 (Visit 2). | Drug: Placebo<br>* Saline control solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Treatment Success: Bayesian Estimated Response Rate | Overall treatment success was determined based on number of responders who had composite response at both months 12 and 24 evaluated per specified criteria. A treatment responder with treatment success was defined as a participant who met the 3 criteria of a composite responder analysis as: 50% or greater reduction in the lower-back pain visual analogue scale (VAS) score; 15-point or greater reduction in the Oswestry Disability Index (ODI) score; and lack of post-treatment interventions at the treated level as of the study visit (Visits 6 [12 months post-treatment] and 8 [24 months post-treatment]). The average response rate (proportion of participants with response presented as Bayesian estimate[BE]) was based upon the average of multiple Bayesian simulations. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness Based on Pain Responders: Bayesian Estimated Response Rate | A participant was defined as a pain responder for a given study visit if they achieved at least a 50% reduction from Baseline in the lower-back pain VAS score (average pain over 24 hours), as reported during in-clinic assessment. The participant should be qualified as a pain responder at both 12 and 24 months post-treatment, and must not have received a post-treatment intervention through 24 months' follow-up. Any participant that did not have a minimum of a visit at 3 months (Study Visit 4) was considered a non-responder for this outcome measure. The average response rate (proportion of participants with response presented as BE) was based upon the average of multiple Bayesian simulations. | Up to 24 months | 
| Effectiveness Based on Functional Responders: Bayesian Estimated Response Rate | A participant was defined as a functional responder for a given study visit if they achieved at least a 15-point reduction from Baseline in ODI score, as reported during in-clinic assessment. The participant should be qualified as a functional responder at both 12 and 24 months post-treatment, and must not have received a post-treatment intervention through 24 months' follow-up; any participant that did not have a minimum of a visit at 3 months (Study Visit 4) was considered a non-responder for this outcome measure. The average response rate (proportion of participants with response presented as BE) was based upon the average of multiple Bayesian simulations. | Up to 24 months | 
| Effectiveness Based on Treatment Success at 24 Months: Bayesian Estimated Response Rate | A treatment responder with treatment success was defined as a participant who met the 3 conditions of a composite responder analysis as: 50% or greater reduction in the lower-back pain VAS score; 15-point or greater reduction in ODI score; and lack of post-treatment interventions at the treated level as of the study visit. The participants qualified as responders if they satisfied the above conditions at the 24-month follow-up visit alone. Any participant that did not have a minimum of a visit at 3 months (Study Visit 4) was considered a non-responder for this outcome measure. The average response rate (proportion of participants with response presented as BE) was based upon the average of multiple Bayesian simulations. | Month 24 | 
| Effectiveness Based on Minimal Pain Responders at 24 Months: Bayesian Estimated Response Rate | A minimal pain responder was defined as a participant who achieved a lower-back pain VAS score (average pain over 24 hours) of 20 mm or less at the given study visit. The participants qualified as responders if they satisfied the above condition at 24 months post-treatment, and did not receive a post-treatment intervention through 24 months' follow-up. Any participant that did not have a minimum of a visit at 3 months (Study Visit 4) was considered a non-responder for this outcome measure. The average response rate (proportion of participants with response presented as BE) was based upon the average of multiple Bayesian simulations. | Month 24 | 
| Effectiveness Based on Time to First Intervention Over 24 Months | The effectiveness of the study drug was evaluated based on its ability in increasing the time to additional interventions at the treated level over 24 months post-treatment. Kaplan-Meier estimates for the probability (expressed as a percentage) of participants to receive an intervention are presented. | Up to Month 24 | 
| Effectiveness Based on Minimal Disability Responders at 24 Months: Bayesian Estimated Response Rate | A minimal disability responder was defined as a participant who achieved an ODI score of 20% or less at the given study visit. The participants qualified as responders if they satisfied the above condition at 24 months post-treatment, and did not receive a post-treatment intervention through 24 months' follow-up. Any participant that did not have a minimum of a visit at 3 months (Study Visit 4) was considered a non-responder for this outcome measure. The average response rate (proportion of participants with response presented as BE) was based upon the average of multiple Bayesian simulations. | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunologic Factors, Chronic Lumbar Back Pain, Low back pain, Back pain, Degenerative Disc Disease, Injection of Degenerated Lumbar Disc, Intervertebral Disc Degeneration, Bone Diseases, Musculoskeletal Diseases, Nervous System Diseases, Neurologic Manifestations, Pain, Spinal Diseases, Stem Cells, Adult Stem Cells, Allogeneic Mesenchymal Precursor cells (MPCs), Mesoblast, Hyaluronic Acid, Pharmaceutical Solutions, Adjuvants, Immunologic, Pharmacologic Actions, Protective Agents, rexlemestrocel-L, Viscosupplements