Efficacy of Intradiscal Injection of Autologous BM-MSC in Worker Patients Affected by Chronic LBP Due to Multilevel IDD

ACTIVE is a phase II B efficacy monocenter, prospective, randomized, controlled double blinded trial, in which intra-discal autologous adult BM-MSC therapy will be compared with sham treated controls.

This trial will evaluate the efficacy of intradiscal injection of autologous BM-MSCs in workers affected by chronic low back pain (LBP) unresponsive to conventional therapy.

The efficacy will be evaluated 12 months after the treatment in terms of pain relief (VAS, Visual Analog Scale), functionality (ODI, Oswestry Disability Index), quality of life (SF36, Short Form - 36) and work ability index (WAI).

Low back pain (LBP) is the main cause of disability in the world, affecting all occupational sectors with different incidence rates. It is estimated that 60 percent of all workers suffer from LBP during their careers, 10 percent of which become chronic (The Lancet. September 2017). Intervertebral disc degeneration (IDD) is widely recognized as a major contributor to LBP, responsible for at least 40 percent of cases. A key characteristic of IDD is loss of matrix integrity and biomechanical functional failure. Today, no therapy can restore intervertebral disc (IVD) function or provide long-term relief from symptomatic IDD. Current therapies are aimed at pain reduction. When these treatments fail, several types of surgery are performed but they are often related to side effects, disturbance of motion and other biomechanical consequences. New strategies concentrate on treating IDD at an early stage. Encouraging results from phase 1 and 2 clinical trials suggest that cell-based regenerative therapies may provide the world first effective therapy for LBP. LBP patients treated with bone marrow mesenchymal stromal/stem cells (BM-MSC) showed rapid and progressive improvement of functional indexes of 65 percent to 78 percent over 1 year after intradiscal administration without side effect. ACTIVE is an ambitious randomized clinical trial aimed at developing a treatment for IDD based on intradiscal injection of autologous BM-MSC to improve the quality of life of workers and the disability of patients with LBP. ACTIVE main aim is to generate efficacy and safety profiles of single injections of 15 million cells/mL of autologous BM-MSC for each disc affected by IDD (up to 4 discs) versus sham procedure. The regenerative potential of BM-MSC treatment will be assessed by Magnetic Resonance Imaging (MRI) technologies on quarterly basis up to 12 months.

Eligibility Criteria:
Inclusion Criteria:

* Workers (it means subject has worked at least 2 months, even if not continuously, in the last 6 months)
* Age between 18 and 65 years.
* Signed informed consent.
* Symptomatic chronic LBP due to moderate/severe IDD \[modified Pfirrmann score 3-5 (Pfirrmann et al., 2001), Griffith score 4-8 (Griffith et al., 2007)\] at max. 4 levels of the lumbar spine unresponsive to conservative treatment, physical and medical for at least 6 months. Physical treatment includes physiotherapy. Medical treatments includes AINS, paracetamol, opioids and myorelaxant.
* Annulus fibrosus intact, demonstrated by MRI.
* Pain baseline \> 40 mm on VAS (0- 100).
* NSAID washout of at least 2 days before screening.
* Painkillers washout of at least 24 hours before screening.
* For females of childbearing potential, a negative pregnancy test must be documented at Screening.
* Men and women should use effective contraception during treatment and for at least 12 months after BM-MSC discontinuation. The complete list of contraceptive methods is described in the patient information sheet and in the paragraph 6.5. As a precautionary measure, breast-feeding should be discontinued during treatment with BM-MSC and should not be restarted after discontinuation of BM-MSC.

Exclusion Criteria:

* Non-workers (it means that the person has worked less than 2 months, although not continuously, in the last 6 months)
* Congenital or acquired diseases leading to spine deformations that may upset cell application (scoliosis, isthmus lesion, sacralization and hemisacralization, degenerative spondilolisthesis).
* Spinal segmental instability assessed by dynamic X-Ray.
* Symptomatic facet joints syndrome on MRI (facet joints hyperintensity and hypertrophy evaluated at coronal T2 weighted MRI).
* Prior to the screening visit, has received:

  * Oral corticosteroid therapy within the previous 3 months, OR
  * Intramuscular, intravenous or epidural corticosteroid therapy within the previous 3 months
* Presence of a 5th level with symptomatic IDD (modified Pfirrmann score 3-5, Griffith score 4-8) in the lumbar spine.
* Spinal canal stenosis (Schizas score \> B).
* History of spinal infection.
* Lumbar disc herniation and sciatica.
* Endplate abnormality such as Schmorl's Nodes.
* Previous discal puncture or previous spine surgery.
* IDD with Modic III changes on MRI images.
* Patients not eligible to the intravertebral disc surgery.
* Patients who have the risk to undergo a surgery in the next 6 months.
* Patients with local infusion device/devices for corticosteroids.
* Obesity with body mass index (BMI in Kg/size in m2) greater than 35 (obesity grade II).
* Participation in another clinical trial or treatment with another investigational product within 30 days prior to inclusion in the study.
* Abnormal blood tests: hepatic (alanine aminotransferase \[ALT\] and/or aspartate aminotransferase \[AST\] \>1.5 × upper limit of normal \[ULN\]), renal, pancreatic or biliary disease, blood coagulation disorders, anemia or platelet count of \<100 × 109/L.
* Pregnant or lactating women, or premenopausal women not using an acceptable form of birth control, are ineligible for inclusion. Contraception will be maintained during treatment and until the end of relevant systemic exposure. Additional pregnancy testing will be performed at the end of relevant systemic exposure. The patients will be required to use contraception from initial treatment administration until 24 months after the last dose of study drug.
* In each case of delayed menstrual period (over 1 month between menstruations), confirmation of absence of pregnancy is strongly recommended. The complete list of contraceptive methods is described in the patient information sheet.
* Positive serology for following infection: Syphilis, HIV, Hepatitis B, or C.
* Contraindication to MRI assessed by the investigator.
* Intolerance or allergy to local anaesthesia.
* Any history of Cancer or immunodeficiency disease.
* Previous transplantation.