A Single Dose of BRTX 100 for Patients With Chronic Lumbar Disc Disease (cLDD)

This is a double-blind, saline-controlled, and randomized study with blinded assessments using a single dose. Subjects that have a current diagnosis of chronic lumbar disc disease and meet eligibility criteria will be enrolled. Chronic lumbar disc disease is defined as back and/or radicular pain with degeneration of the disc confirmed by patient history, physical examination, and radiographic measures such as computed tomography (CT), magnetic resonance imaging (MRI), plain film, myelography, discography, or other acceptable means.

This is a double-blind, saline-controlled, and randomized study with blinded assessments using a single dose. Subjects that have a current diagnosis of chronic lumbar disc disease and meet eligibility criteria will be enrolled. Chronic lumbar disc disease is defined as back and/or radicular pain with degeneration of the disc confirmed by patient history, physical examination, and radiographic measures such as computed tomography (CT), magnetic resonance imaging (MRI), plain film, myelography, discography, or other acceptable means.

Subjects randomized to active treatment will undergo bone marrow harvest for processing into BRTX-100 for intradiscal injection. Subjects randomized to control will also undergo a bone marrow and blood harvest but only receive saline intradiscal injection procedures. Subjects will return to the study site for a visit at Week 2, Week 12, Week 26, Week 52 and Week 104/Early Termination.

The trial will have a Safety Run-In component that will insert a 3+3 design for the initial subjects dosed with BRTX-100 at 40 × 106 cells. Specifically, the randomization scheme will be briefly shifted from the overall trial 2:1 randomization to an initial 3:1 allotment of intradiscal BRTX-100 versus saline control. As such, four subjects will initially be randomized and administered their agents. There will be a 14 day safety follow-up period that must elapse between dosing of each of the first four (4) subjects. Dosing of each subsequent subject in the Safety Run-In component cannot occur until the independent Medical Monitor (MM) reviews the previously-dosed subject's blinded data, including but not limited to physical examination findings, laboratory values and reported adverse events (AEs) and serious adverse events (SAEs), at the completion of the 14-day visit and documents the findings. If no potential dose- limiting toxicity (DLT) is noted by the MM, the MM will approve the dosing of the next subject. If a potential DLT is noted by the MM, the MM will request that an ad hoc Data Safety Monitoring Board (DSMB) review of unblinded data occur per DSMB Charter before the next subject is dosed.

Eligibility Criteria:
Subject Inclusion Criteria:

A subject is eligible for inclusion if all the following criteria are met:

1. A high index of suspicion for discogenic pain, (i.e., painful degenerative disc(s) with or without protrusions \< 5 mm)

   1. Chronic Lower Back Pain for at least 6 months
   2. Pain commonly provoked by prolonged sitting, forward bending, lifting, twisting, coughing, sneezing, or Valsalva maneuvers
   3. Failure of at least 6 months of conservative back pain care (can include any or all of the following: rest, anti-inflammatory medication, analgesics, narcotics, epidural injections or selective nerve root injections at the target level, facet joint injections, muscle relaxers, massage, acupuncture, chiropractic care)
   4. Failure of supervised therapy and education
   5. Screening of ≥ 40 mm and ≤ 80 mm on low back pain visual analog scales (VAS) (average pain in the last week)
   6. Screening Oswestry Disability Index (ODI) score ≥ 30 and \< 90 on a 100-point scale
   7. No localized and significant pain below beltline (i.e., potential sacroiliac joint pain) without lumbar pain component
   8. Thigh or Leg pain, if present, is non prevailing and of nonradicular origin, i.e., not due to stimulation of nerve roots or dorsal root ganglion of a spinal nerve by compressive forces
   9. Diagnostic medial branch block or facet joint injection (bilateral unless the symptoms are purely unilateral in nature) in the last 12 months prior to the informed consent date indicates no prevailing facet joint involvement
2. Has degenerative disc disease (DDD) as defined by the following:

   1. Changes from normal disc morphology of the affected disc as defined by radiographic evaluation
   2. Modified Pfirrmann score of 2 to 7 on MRI, may contain a contained protrusion and/or annular tear on MRI
   3. Modified Pfirrmann score of 1 must contain a contained protrusion and/or annular tear on MRI
   4. Modic Grade I or II changes or no change on MRI
   5. Maintained intervertebral disc heights of at least 50% on MRI.
   6. Discography, if not performed within the last 6 months prior to informed consent date, has to be performed if more than one degenerative disc is identified by MRI, and the symptomatic disc cannot be otherwise reasonably determined
   7. If more than one degenerative disc is identified by MRI, no disc shall demonstrate greater degenerative change than the symptomatic disc or contain a protrusion greater than 5mm
3. Aged 18 to 60 years
4. Willing and able to provide written informed consent
5. No evidence of contraindications to the procedure such as pregnancy, active infection, bleeding disorder, or metastatic cancer.

Subject Exclusion Criteria

A subject is not eligible to participate if any of the following criteria are met:

1. Spinal Deformity (Scoliosis \>20 degrees, spondylolysis, clinically or radiographically significant retrolisthesis or spondylolisthesis) detected on MRI or plain film radiographic assessment
2. Disc extrusions, sequestered fragments, facet cysts, or greater than moderate spinal stenosis on MRI.
3. Presence of a Grade V annular fissure on discography in a subject for whom provocation discography has been performed
4. Intervertebral disc with radiographic evidence of Modified Pfirrmann Grade 8 or greater
5. Any bleeding disorder, intrinsic or extrinsic
6. Required anticoagulation (with either antiplatelet agents or antithrombotics) that cannot be interrupted for harvest and injection procedures
7. Platelet count \< 100,000
8. International Normalized Ratio (INR) \> 1.5
9. Extreme obesity, as defined by National Institute of Health (NIH) Clinical Guidelines Body Mass Index (BMI \>40
10. Clinically relevant instability on flexion-extension as determined by the investigator by overlaying films (flexion \& extension films)
11. Has undergone any previous lumbosacral spine surgery (e.g. discectomy, laminectomy, foraminotomy, fusion, intradiscal electrothermal therapy, intradiscal radiofrequency thermocoagulation.) or therapeutic percutaneous disc intervention
12. Have any acute or chronic lumbosacral spine fracture
13. Have a history of lumbosacral epidural steroid injections within 1 month prior to informed consent date.
14. Planned/expected use of systemic non-steroidal anti-inflammatory drugs (NSAIDs) within 72 hours prior to study treatment.
15. Have a known history of hypersensitivity or anaphylactic reaction to dimethyl sulfoxide (DMSO)
16. Active significant non lumbosacral spinal orthopedic pain generators including, not limited to arthritic hip and/or knee, cervical disc disease
17. More widespread and ill-defined myofascial pain
18. Have had treatment with any cellular or biological investigational therapy or device within 6 months of informed consent date and/or plans to participate in any other autologous or allogeneic stem cell/progenitor cell therapy trial during the 2-year follow-up period.
19. Have been a recipient of prior stem cell/progenitor cell therapy or other biological intervention to repair a lumbosacral intervertebral disc
20. Are transient or has been treated in the last 6 months before enrollment for alcohol and/or drug abuse in an inpatient substance abuse program
21. Apparent ongoing and poorly controlled psychological or somatic disease that may impact treatment outcomes
22. Social, familial, or geographical hindrances to compliance with the study protocol or the informed consent process.
23. Known autoimmune disease (e.g., systemic lupus erythematosus)
24. Required chronic immunosuppression
25. Positive hepatitis C virus (HCV) antibody test
26. Positive human immunodeficiency virus (HIV) Ag/Ab Combo test
27. Pregnant or lactating women
28. Women of childbearing potential not protected by a highly-effective method of birth control
29. Clinically significant hematology and chemistry including, but not limited to: a. Total bilirubin level ≥ 1.5 times institutional upper limit of normal (ULN) b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2 x ULN c. Absolute neutrophil count (ANC) \< 1000/mm3 d. Hemoglobin ≤ 10 g/dL e. Creatinine clearance use calculated clearance (Cockcroft-Gault equation) of ≤ 50 mL/min
30. Any other condition which in the judgment of the Investigator would preclude adequate evaluation of the safety and efficacy of the study drug
31. Inability to comply with the requirements of the study protocol
32. History of using nicotine delivery products (active within 3 months of study treatment prior to informed consent date)
33. Actively on workers compensation or no-fault case for this complaint or any other active case or litigation pertaining to their lumbosacral pain
34. History of drug abuse or documented history of noncompliance with controlled substances
35. History of regular, long term, daily opioid drug use (\>30 MME)