Intervertebral Disc Regeneration Mediated by Autologous Mesenchymal Stem/Stromal Cells Intradiscal Injection: a Phase IIB Randomized Clinical Trial - DREAM Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 52
- 试验地点
- 1
- 主要终点
- Pain Change
研究概览
简要总结
DREAM is a phase II B efficacy monocentric, prospective, randomized, controlled double blinded trial, comparing intra-discal autologous adult bone marrow mesenchymal stem cells (BM-MSC) therapy and sham treated controls in subjects with chronic (> 6 months) Low Back Pain (LBP) due to lumbar multilevel (max. 3 levels) intervertebral disc degeneration (IDD) unresponsive to conventional therapy.
Duration of the recruitment period has been estimated to be 12 months. The efficacy of intradiscal injection of autologous BM-MSC in reducing chronic LBP due to multilevel lumbar IDD will be evaluated after 24 months in terms of pain relief (VAS), functionality (ODI) and quality of life (SF36).
详细描述
Low back pain (LBP) is the global leading cause of disability, and furthermore rates sixth in terms of overall disease burden, in both developed and developing countries. LPB is a condition of all ages, from children to elderly, affecting 60-70 percent of the global population during life, and ~700 million people each year. LBP prevalence increases with age, and with populations ageing worldwide, the societal and economic burden associated with LBP will increase substantially over coming years.
Current LBP therapies are aimed at pain reduction, and do not provide restorative treatment. Such conservative strategies (e.g. painkillers and musculoskeletal rearrangement by manual and physiotherapy) rarely address the actual cause of LBP.
In a healthy spine, intervertebral discs (IVDs) separate the vertebrae to provide complex spinal flexibility while supporting large spinal loads. Intervertebral disc degeneration (IDD) is widely recognized as a major contributor to LBP, responsible for at least 40 percent of LBP cases. A key characteristic of IVD degeneration is loss of matrix integrity, thereby causing biomechanical functional failure.
Today, no therapy can restore IVD function or provide long-term relief from symptomatic IDD. New treatment strategies concentrate on treating IDD at an early stage. Stem cell research offers exciting possibilities, and advanced cell-based therapies are considered highly promising strategies in treating IVD degeneration and LBP. Encouraging results suggest that cell-based, regenerative therapies may provide the world first effective therapy for this common and debilitating disease.
The objective of DREAM is to generate efficacy and tolerability profiles of a single injection of 15 million of cells/ml of autologous BM-MSC for each disc affected by IDD (up to 3 discs) versus sham procedure. The potential of BM-MSC to lead to a disease-modifying therapeutic option for the treatment of this chronic and debilitating disease will be assessed by Magnetic Resonance Imaging (MRI) after 6 months, 1 and 2 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
盲法说明
The randomization will be centralized and stratified on the investigation center. Treatment allocation will be performed 24 hour-a-day online by a central randomization web-service. The patient identification must be unique within all randomizations performed. For double-blind trial the randomization result will be a treatment code. Blinding or masking will be carried out at all stages of packaging and conditioning for shipping following the treatment allocation. Injections used for all groups will be clear and indistinguishable from each other.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent.
- •Symptomatic chronic LBP due to moderate IDD (modified Pfirrmann score 3-4, Griffith score 3-7) at max.3 levels of the lumbar spine unresponsive to conservative treatment, physical and medical for at least 6 months. Physical treatment includes physiotherapy. Medical treatments includes nonsteroidal anti-inflammatory drugs (NSAID), 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 24 months after BM-MSC discontinuation. As a precautionary measure, breast-feeding should be discontinued during treatment with BM-MSC and should not be restarted after discontinuation of BM-MSC.
排除标准
- •Congenital or acquired diseases leading to spine deformations that may upset cell application (scoliosis, isthmus lesion, sacralization and hemisacralization, degenerative spondylolisthesis).
- •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 4th level with symptomatic IDD (modified Pfirrmann score 3-4, Griffith score 3-7) 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 II and 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 m^2) 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 amino transferase [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 × 10^9/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 one month between menstruations) confirmation of absence of pregnancy is strongly recommended.
- •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.
研究组 & 干预措施
Active Arm
Two procedures:
- Bone marrow harvesting from the posterior superior iliac crest region
- Single injections of a dose of 15 million of autologous BM-MSC for each disc affected by IDD (up to 3 discs) via imaging control
干预措施: Autologous BM-MSC (Drug)
Sham Procedure
Two sham procedures:
- Simulated bone marrow harvesting without insertion into the posterior iliac crest region
- Simulated injection under only local anaesthesia without disc injection and without placebo injection.
干预措施: Sham (Procedure)
结局指标
主要结局
Pain Change
时间窗: From Baseline to Month 24
Changes in pain will be evaluated on Visual Analogic Scale (VAS) between baseline and month 24. VAS scale ranges from 0 to 100, where 0 represents no pain and 100 represents the worst pain imaginable.
Functional disability index evaluation
时间窗: From Baseline to Month 24
Functional disability changes will be assessed on Oswestry Disability Index (ODI, also known as the Oswestry Low Back Pain Disability Questionnaire) at month 24 compared with baseline. ODI scale ranges from 0 to 50 and allows evaluation of disability (0 - 20 percent: minimal disability; 20 - 40 percent: moderate disability; 40 - 60 percent: severe disability; 60 - 80 percent: crippled; 80 - 100 percent: bed-bound or exaggerating their symptoms).
次要结局
- Quality of life evolution(Baseline, 3, 6, 12 and 24 months)
- Drug consumption of rescue painkillers medication(Baseline, 3, 6, 12 and 24 months)
- Structural assessment(Baseline, 6, 12 and 24 months)
- Coagulation status: safety parameter(Baseline, 3, 6, 12 and 24 months)
- Metabolic functions: safety parameter(Baseline, 3, 6, 12 and 24 months)
- Inflammation: safety parameter(Baseline, 3, 6, 12 and 24 months)
- Disability evolution(Baseline, 3, 6, 12 and 24 months)
- Employment and work status assessment(Baseline and 24 months)
- Measurement of pain(Baseline, 3, 6, 12 and 24 months)
- Evaluation of costs(12 and 24 months)
- Body Mass Index evaluation(Baseline, 3, 6, 12 and 24 months)
- Haematological evaluation: safety parameter(Baseline, 3, 6, 12 and 24 months)
- Urinalysis(Baseline, 3, 6, 12 and 24 months)
- Spine examination(Baseline, 3, 6, 12 and 24 months)
- Specific Adverse Events Evaluation(Baseline, 3, 6, 12 and 24 months)