Phase IIB Randomized Trial of Intradiscal Injection of Autologous Bone Marrow Mesenchymal Stem Cells for Chronic Low Back Pain Due to Multilevel Lumbar Intervertebral Disc Degeneration

The primary objective of this study is to evaluate the **effectiveness** of intradiscal injection of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in reducing chronic low back pain (LBP) due to multilevel lumbar intervertebral disc degeneration (IDD) after 12 months of treatment. This will be assessed in terms of pain relief using the Visual Analog Scale (VAS), functionality using the Oswestry Disability Index (ODI), and quality of life using the SF-36 questionnaire. The clinical relevance of this objective lies in addressing the debilitating effects of chronic LBP, which significantly impacts patients' quality of life and functional capacity.

Secondary objectives include:

• Evaluating regenerative changes of the treated intervertebral disc (IVD).
• Assessing modification of employment and work status between baseline and 12 months.
• Assessing safety and tolerability of the treatment.
• Evaluating the consumption of medications to relieve pain, including the type and dose of analgesics.

The clinical trial focuses on evaluating the effectiveness of intradiscal injection of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in reducing chronic **low back pain** due to multilevel lumbar intervertebral disc degeneration. The study population includes both male and female participants aged between 18 and 65 years, who are experiencing symptomatic chronic low back pain unresponsive to conservative treatments for at least six months. Participants must have an intact annulus fibrosus as demonstrated by MRI and a baseline pain score greater than 40 mm on the Visual Analogue Scale (VAS). The trial does not involve a vulnerable population. Lifestyle considerations include a washout period for NSAIDs and painkillers before screening. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the effectiveness of **intradiscal injection** of autologous bone marrow mesenchymal stem cells (BM-MSCs) in reducing chronic low back pain (LBP) due to multilevel lumbar intervertebral disc degeneration (IDD). This is a phase IIB randomized, double-blind, controlled trial. The trial aims to assess pain relief, functionality, and quality of life over a 12-month period. Participants will be randomly assigned to receive either the BM-MSC treatment or a control intervention, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the study.

The trial will commence with a screening visit to determine eligibility based on specific inclusion criteria, such as age between 18 and 65 years, symptomatic chronic LBP due to moderate IDD, and an intact annulus fibrosus as demonstrated by MRI. Participants must also have a baseline pain score greater than 40 mm on the visual analog scale (VAS) and must undergo a washout period for NSAIDs and painkillers prior to screening. Females of childbearing potential must have a negative pregnancy test at screening and use effective contraception during and after the study.

Following the screening, eligible participants will undergo baseline assessments before receiving the assigned treatment. Follow-up visits are scheduled at 1, 3, 6, and 12 months post-treatment to evaluate primary and secondary endpoints. These include changes in pain and functional status using VAS and the Oswestry Disability Index (ODI), as well as quality of life assessments using the SF-36 scores. Quantitative MRI signal measurements will be used to assess changes in the treated intervertebral discs. Safety and tolerability will be monitored throughout the study by recording adverse events and serious adverse events.

The expected duration of participant involvement is approximately 12 months, with the trial estimated to conclude by March 2025. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or non-compliance with study protocols. The trial's primary endpoint is to determine the efficacy of the BM-MSC treatment, defined as at least a 30% improvement in VAS or ODI at 12 months compared to baseline. Secondary endpoints include the evaluation of medication consumption for pain relief and the overall safety profile of the treatment.

The clinical trial involves the use of **ex vivo expanded autologous human corneal epithelial cells containing stem cells** as the experimental medication. This product, known as **Limbal Stem Cells, Autologous**, is classified under the ATC code S01XA19. The pharmaceutical form of the product is designated as PHF00283MIG. The administration route for this treatment is via **injection**. The maximum daily dose is set at 15 million international units (IU), with the same amount being the maximum total dose. The treatment period is limited to a maximum of one day. The product is not formulated for pediatric use and is not classified as an orphan drug.

In addition to the experimental treatment, the study also involves the use of **Autologous Bone Marrow Mesenchymal Stem Cell** as a non-experimental treatment. This serves as a comparator treatment to evaluate the effectiveness of the experimental medication. The administration details, including dosage and frequency, for this comparator treatment are not specified in the provided data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on evaluating the efficacy of intradiscal injection of autologous bone marrow mesenchymal stem cells (BM-MSC) using the visual analog scale (VAS) for pain and the Oswestry Disability Index (ODI) for functional status. Responders are defined as participants who achieve at least a 30% improvement in VAS or ODI at month 12 compared to baseline.

Secondary endpoints include evaluating changes in the treated intervertebral disc (IVD) through quantitative Magnetic Resonance Imaging (MRI) signal measurements in T2, assessed at baseline and at 1, 3, 6, and 12 months. Additionally, modifications in disability (ODI) and pain relief (VAS) will be measured as continuous variables at baseline and at 1, 3, and 6 months. Quality of life will be assessed using the SF-36 scores, and work ability will be evaluated using the Work Ability Index (WAI) at baseline and at 1, 3, 6, and 12 months.

Safety and tolerability will be monitored by recording adverse events (AEs) and serious adverse events (SAEs) throughout the study until 12 months. The number of participants experiencing adverse events, the correlation of these events to the investigational medicinal product (IMP), and their severity will be used as measures of safety and tolerability. Additionally, the consumption of medications for pain relief, including the type and dose of analgesics such as paracetamol (acetaminophen) and level 2 analgesics, will be evaluated at each visit throughout the study.