| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Degenerative Disc Disease |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10070241 |
| E.1.2 | Term | Degenerative disc disease |
| E.1.2 | System Organ Class | 100000004859 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Co-Primary objectives: The first objective is to assess of intradiscal injection of allogeneic BM-MSCs in reducing chronic low back pain due to lumbar DDD using the visual analog scale (VAS) and functional status assessed by the Oswestry disability index (ODI) after 12 months of treatment, defining a responder as a patient with an improvement of VAS for pain of at least 20% and 20 mm between baseline and month 12, or with an improvement of ODI of 20% between baseline and month 12. The second objective is to assess disc fluid content, measured by quantitative Magnetic Resonance Imaging, between baseline and month 12 afetr BM-MSC injection.
the study will be considered a success only if the 2 objectives are acheived (Multiple Endpoints in Clinical Trials, Guidance for Industry, FDA 2017).
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of intradiscal injection of allogeneic BM-MSCs using VAS and ODI after 3, 6 and 24 months of treatment … (see protocol p. 35)
• Assess efficacy of allogeneic stem cell treatments for DDD on modification of ...
• Evaluate modification of disability (ODI) and quality of life (SF-36 scores), considered as continuous measures, between baseline and 3, 6, 12 and 24 months.
• Evaluate modification of affected disc by ... (see protocol p. 35)
• Assess modification of employment and work status between baseline and months 12 and 24.
• Assess safety and tolerability, measured by (see protocol p. 35)
• Consumption of medications to relieve pain such as (see protocol p. 35)
• Assess immune response associated with allogeneic cells injection (quantification of anti-HLA in all patients).
• Assess the safety of local MSC injection on (see protocol p. 35)
• Assess the medical and non-medical costs
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The biological effect of the MSC injection on recipient immune response assessement for 60 patients
Obj : Assess the safety of local MSC injection on the systemic immune system (sub-study)
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| E.3 | Principal inclusion criteria |
- Age between 18 and 60 years at pre-screening visit.
- Symptomatic chronic low back pain unresponsive to conservative therapy (including physical therapy performed during at least 1 month before inclusion and pain medication with level 2 analgesics in failure or intolerant to level during at least 1 month) for at least 3 months.
- DDD assessed by (Pfirrmann’s score modified Griffith et al) grade 4 to 7 at one level. If second level, it should be adjacent (Pfirrmann’s score 1-4 maximum)
- Low back Pain at screening > 40 mm on VAS (0-100).
- NSAID washout of at least 2 days before screening
- Painkillers washout of at least 24 hours before screening |
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| E.4 | Principal exclusion criteria |
- Congenital or acquired diseases leading to spine deformations that may upset cell application (hyperlordosis, scoliosis, isthmus lesion, sacralisation and hemisacralisation).
- Symptomatic posterior lumbo-articular osteoarthritis or predominant facet syndrome on Xray or MRI (osteophyte and facet hypertrophy).
- 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
- Spinal segmental instability (defined by lumbar dynamic X-Ray in extension/flexion with antero-post translation > 3 mm and/or angular mobility > 15°).
- Spinal canal stenosis (Schizas score > B).
- History of spinal infection.
- History of lumbar disc herniation with non truncated sciatica or cruralgia, as well as lumbar cysts and radiculopathy
- Previous discal puncture or previous spine surgery.
- DDD on 3 levels, or DDD on 2 levels but not adjacent, or DDD with modic 2 or 3 phases
- Patients contre-indicated to intravertebral disc rescue surgery
- Patients who have the risk to undergo a surgery in the next 6 months
- 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.
- Significant medical problems, such as uncontrolled hypertension, symptomatic heart failure; or any other clinically relevant condition or current medication that in the opinion of the investigator contra-indicates the use of any of the study or rescue medications.
- Pregnant or lactating women, or premenopausal women not using an acceptable form of birth control, are ineligible for inclusion. Contraception has to be maintained during treatment and until the individual end of the study (M24). In each case of delayed menstrual period (over one month between menstruations) confirmation of absence of pregnancy is strongly recommended. Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include:
- combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation : oral, intravaginal, transdermal
- progestogen-only hormonal contraception associated with inhibition of ovulation : oral, injectable, implantable
- intrauterine device (IUD)
- intrauterine hormone-releasing system ( IUS)
- bilateral tubal occlusion
- vasectomised partner
- sexual abstinence are ineligible for inclusion.
- Positive serology for following infection: Syphilis, HIV, Hepatitis B, or C.
- Contraindication to MRI assessed by the investigator.
- Intolerance or allergy to local anesthesia.
- Any history of Cancer or immunodeficiency disease.
- History of transfusion or transplantation.
- Current sick leave due to work accident.
- Prisoners or subjects who are involuntary incarcerated.
- Patients subject to legal protection measures. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The clinical response is defined as pain relief of at least 20% and 20 mm decrease on VAS scale between baseline and month 12, or 20% improvement of functional index ODI at month 12 compared to baseline. Chronic low back pain is assessed using the VAS pain scale (0 – 100, where 0 represents no pain and 100 represents the worst pain imaginable). ODI scale ranges from 0 to 50 and allows evaluation of disability (0% – 20%: minimal disability; 20% – 40%: moderate disability; 40% – 60%: severe disability; 60% – 80%: crippled; 80% – 100%: bed-bound or exaggerating their symptoms).
Fluid content of the discs will be determined from T2-weighted sagittal images, and measured in the affected disc segment and in the contiguous 3 to 5 segments (Methods and Orozco et al). The fluid content values of the affected discs will be normalized to the values obtained from the healthy discs in the same individual (average value of the healthy discs). The change in fluid content is expressed as the ratio of fluid content at months 12 vs fluid content at baseline.
Evolution of affected disc(s) by quantitative Magnetic Resonance Imaging (MRI) density measurements in T2 and T1spin/echo and T1rho weighted images performed at screening, 6 12 and 24 months used as an indication of disc fluid and GAG content. The "quality" of the patient's lumbar disc will be monitored non-invasively using T2-weighted MRI sagittal images (Orozco et al., 2011) (http://www.citospin.com/MESODISC/Fig_S3_.pdf) and, in T1spin/echo MRI. Lumbar disc grading will be performed in the sagittal T2 weighted images by two physicians independently who were experienced in MRI of the spine. They will review each intervertebral disc from L1–2 to L5-S1 by the modified Pfirrmann’s criteria. The modified Pfirrmann’s grading system assesses degenerated intervertebral discs by MRI for the asymmetry in disc structure, distinction of the nucleus and the annulus, signal intensity of intervertebral discs and height of intervertebral discs and assigns grade 1 to 8 for disc degeneration (Table by Griffin et al. Spine 2007).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Disability and quality of life evolution include Short Form (SF)-36 scores, global assessment by the patient and the physician. Overall pain intensity in the lumbar spine (1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = extreme); patient's global assessment of disease activity (1 = very good, 2 = good, 3 = fair, 4 = poor, 5 = very poor); physician's global assessment of disease activity (1 = very good, 2 = good, 3 = fair, 4 = poor, 5 = very poor) will be performed at 0, 1, 3, 6, 12 , 24, 36, 48, 60 months.
Additionally we will assess: de-/increase in rescue painkillers medication. Rescue medication use will be recorded throughout the study duration by a diary file. During the treatment phase of the study, a daily maximum of 3 g paracetamol/acetaminophen will be permitted. Opioid intake will be possible if paracetamol/acetaminophen is not sufficient. Only tramadol will be authorized.
Pain
The measurement of pain will be determined by self-report of current pain in rest and in motion in the low back pain using a VAS scale. In brief, the VAS consisted of a 10 cm horizontal line anchored with descriptors of pain including "no pain" on one end (left) and "extreme pain" on the other (right). After sitting for 10 minutes, subjects struck a vertical line through the 10 cm VAS representing their CP, and the distance from left end (no pain) to the vertical line was recorded in centimetres. In addition, the patients will fill VAS tests indicating the amount of pain experienced at rest, and in motion.
The drug consumption of painkillers will be assessed throughout the study at each visit. A diary file containing doses, drug name and indication will be given to each patient. The investigator will control this book at each visit. A reduction in dose or frequency of administration of painkillers is an indirect marker of the benefits of MSC therapy.
Employment and work status will be assessed. For this we will assign each of the patients to one of 4 categories designated as “employable” which included those who were unemployed due to pain, employed but on sick leave, laid off, or working. The other categories include retired, disabled, and elderly at least 60 years of age, eligible for social security.
Evaluation of cost:
We will compare the medical and non-medical costs between the two groups of patient. Costs will be identified for a one-year time horizon.
For this purpose, resource use in each arm will be collected in physical units in the eCRF at each clinical centre as follows:
- Acute care medical hospitalisations related to DDD
- Acute care surgical hospitalisations related to DDD
- Rehabilitation hospitalisations related to DDD
- Analgesics
- Work disruption
Resource use will be valued using production costs specific to each country or to the country having included the highest number of patients, depending on the number of patients actually included in each clinical centre.
Immune response / Analytical control
Although originally the beneficial effect of MSC was thought to be through engraftment and regeneration, subsequent studies demonstrated that the main therapeutic effects may be mediated primarily through the secretion of soluble factors and their impact on immune cells. Indeed, MSC have been shown to (1) inhibit the differentiation and activation of T cells (2) promote induction of immunosuppressive FoxP3+ T-regulatory cells, (3) induce Breg cells (4) impact DC and macrophage differentiation. In this project, the use of allogeneic MSC and their putative impact on immune cells sustains the need to monitor the recipient immune response. The assessment of the biological effect of allogeneic MSC on recipient immune response will be studied by multiparametric flow-cytometry as well as monitoring of anti HLA-I antibodies response. As nucleus pulposus (NP) is an immuno privileged tissues, without vascularisation, so we do not expect cell rejection. However, selection of patient according to the presence of initial antiHLA Ab in the serum is critical as well as follows up of allo response in case we will need further cell injection in the future. We will perform the HLA-genotyping of MSCs and will assess MSC immunogenicity investigating the emergence of anti-HLA class 1 antibodies in all patients before and after treatment.
This large-scale immunomonitoring is optional and will be performed on 60 patients. The immunomonitoring will be possible on the two standardized platforms of the ECELLFRANCE infrastructure (the first located in Rennes under the supervision of Pr Karin Tarte and the second located in Montpellier, Pascale Louis-Plence). The two platforms have been already involved in the immunomonitoring of the MSC-recipients in previous phase 1 clinical trials (ADIPOA 1, SCLERODERMIA) and will be ... (more see protocol p. 38)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
0, 3, 6, 12 and 24 months
36, 48, 60 months (VAS, ODI, SF-36) |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Control group with a sham procedure |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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