E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients diagnosed with symptomatic degenerative spondylolisthesis grade I or II with an indication for spinal fusion of one vertebral segment (L1-S1). |
Pacjenci z objawowym kręgozmykiem zwyrodnieniowym niskiego stopnia - I lub II stopień, poddawanych operacji fuzji międzytrzonowej jednego segmentu kręgowego (L1 - S1) |
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E.1.1.1 | Medical condition in easily understood language |
Patients diagnosed with symptomatic degenerative spondylolisthesis grade I or II with an indication for spinal fusion of one vertebral segment (L1-S1). |
Pacjenci z objawowym kręgozmykiem zwyrodnieniowym niskiego stopnia - I lub II stopień, poddawanych operacji fuzji międzytrzonowej jednego segmentu kręgowego (L1 - S1) |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10077991 |
E.1.2 | Term | Lumbar spondylolisthesis |
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 |
To evaluate the safety (local and systemic) of a specific surgical intervention with the use of NVD-001 (AEs, AESI, SAEs) in patients with symptomatic low-grade degenerative spondylolisthesis grade I or II undergoing surgery for spinal fusion of one vertebral segment (L1-S1). |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the safety (local and systemic) of a commonly used surgical intervention with the use of locally harvested cancellous bone (laminectomy).
• To determine the clinical efficacy of one level spinal lumbar interbody fusion with NVD 001by imaging assessments.
• To determine the clinical efficacy of one level spinal lumbar interbody fusion with locally harvested cancellous bone by imaging assessments.
• For both groups:
- Functional assessment
- Pain assessment
- Subsequent surgical interventions (revision, removal, reoperation and supplemental fixation)
• For both groups:
- To record peri- and postoperative blood loss
- To record duration of surgery
- To record the number of postoperative hospital days stays
- To assess Overall Treatment effect evaluation
- QoL assessment |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject has understood and accepted to participate in the study according to all study procedures by signing the approved informed consent.
2. Male or female subjects aged ≥18 and skeletally mature (epiphyses closed) at Visit V0a.
3. Subject has clinically important pain or neurological symptoms at V0a with or without claudication due to symptomatic degenerative spondylolisthesis grade I or II (Meyerding Classification: see Appendix A).
4. Conservative treatment of disease has failed for at least 3 months since diagnosis. (ISASS 2011)
5. Subject has a preoperative ODI score >30.
6. Subject has an indication for spinal fusion of one vertebral segment (L1-S1) due to symptomatic degenerative spondylolisthesis grade I or II diagnosed by computed tomography (CT) scan and/or magnetic resonance imaging (MRI) and/or dynamic radiography.
7. Subject is suitable for surgical operation and incorporation of the PEEK cage(s) by transforaminal lumbar interbody fusion (TLIF) or posterior lumbar intervertebral fusion (PLIF) by minimally invasive or open approach in one mobile segment (L1- S1) with bilateral rigid fixation. No posterolateral lumbar fusion (PLF) technique is allowed.
8. Subject is, in the Investigator’s opinion, psychosocially, mentally and physically able to fully comply with this protocol, including the postoperative regimen and follow-up visits.
9. At screening, local laboratory safety test results are clinically acceptable and serology results for HIV, HBV, HCV, HTLV I/II and syphilis are in accordance with country specific requirements for donation of Human Body Material. At time of adipose tissue collection, central laboratory serology and molecular test panel for HIV, HBV, HCV, HTLV I/II and syphilis must be in accordance with Belgian specific requirements for release of Human Body Material. (see Appendix B).
10. Women of childbearing potential (WOCBP) including peri-menopausal women who have had a menstrual period within 1 year prior to surgery have to have a negative pregnancy test. Results have to be available and negative for the patient to be entered in the study. 11. WOCBP have to use an effective method of birth control 2 months prior to study entry or to surgical intervention date and throughout the study duration (defined as a method which results in a failure rate of less than 1% per year) such as:
-Combined (oestrogen 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 (provided that partner is the sole sexual partner of the trial participant and that the surgical success of vasectomy has
been confirmed)
-Sexual abstinence
For each case of delayed menstrual period, confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to WOCBP with infrequent or irregular menstrual cycles. In case a urine pregnancy test is positive, a confirmatory blood pregnancy test is obligatory |
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E.4 | Principal exclusion criteria |
1. Subject has known history of hypersensitivity or anaphylactic reaction to PEEK.
2. Due to medical or other reasons spine fusion cannot be delayed for up to 6 months.
3. Indications for spinal fusion other than symptomatic degenerative spondylolisthesis grade I and II (Meyerding Classification: see Appendix A).
4. Subject displays drug or alcohol dependence, serious current illness, mental illness or extenuating circumstance or any other factors which, in the opinion of the Investigator, will interfere with study conduct or interpretation of the results.
5. Subject has documented metabolic disease such as but not limited to severe osteoporosis, osteogenesis imperfecta or osteomalacia.
6. Subject with poorly controlled diabetes mellitus as assessed by glycohaemoglobin (HbA1c) >8% (at least 2 values per year for last 2 years).
7. Subject is underweight, i.e. body mass index (BMI) ≤18.5 or has a BMI of ≥40, or ≥35 and experiencing obesity-related health conditions, such as high blood pressure or diabetes at V0a.
8. Overt or active local or systemic infection, including latent infection around (area of) the future surgical implant site.
9. Subject has a history of previously attempted spinal fusion at the same level, or spine level immediately adjacent to the level to be operated on in this study. Decompressive surgery alone (laminectomy) is not an exclusion criterion.
10. Subject is on a transplant list or having received a solid organ transplant at any point in the past.
11. Pregnant or breast-feeding woman.
12. Involved in or planning to engage in litigation-related health problems.
13. Subject is a prisoner.
14. Subject had an acute fracture of the spine within 6 months prior to V0a in the study.
15. Subject is known to require additional surgery to the lumbar spinal region within the next 2 years after enrolment in the study.
16. Subject is currently taking chronically any medications that might affect bone metabolism or the quality of bone formation such as but not limited to bisphosphonates, steroids, methotrexate, anticoagulant therapies, immunosuppressants or immunotherapy.
17. Subject is currently using an electrical bone growth stimulator.
18. Subject is positive for human immunodeficiency virus (HIV) 1 or 2, hepatitis B (HBsAg or PCR positive) or C, human T-cell lymphotropic virus (HTLV) 1 or 2, or syphilis at screening (V0a).
19. Subject was exposed to any experimental therapy with another investigational drug within 60 days prior to screening or enrolment in any concurrent study that may confound the results of this study.
20. Subject previously received a cellular therapy (at any point in time).
21. Subject was exposed to therapy for a malignancy or pre-malignant entity, and not confirmed disease-free for 5 years or more.
22. Any clinically relevant chronic disease associated with renal or hepatic insufficiency or any chronic disease of such severity that surgery could be detrimental to the survival of the patient.
23. Any other illness which might reduce life expectancy to less than 2 years from screening.
24. Subject is on chronic immunosuppressive therapy (immunosuppressants/immunotherapy) due to inflammatory or systemic disease.
25. Subject has an active inflammatory systemic autoimmune disease that could interfere with bone metabolism such as but not limited to rheumatoid arthritis, ankylosing spondylarthritis, inflammatory bowel disease, systemic lupus erythematosus or thyroid diseases. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Collecting all adverse events for incidence, severity, relatedness, required action and outcome.
• Collecting all SAEs (also SAEs during second year follow-up)
• Collecting Adverse Events of Special Interest (AESI) (also at 24 months post-surgery) as part of local and systemic toxicity such as
o Signs of local toxicity of experimental product will be evaluated on CT and radiographic images by independent radiologist and include:
• Trabecular bone resorption
• Intravertebral cystic changes
• Soft tissue calcification/ossification
• Peridiscal soft tissue swelling
• Hyperostosis
• Tumour growth
o Signs of systemic toxicity will be evaluated on chest radiographs and include appearance of calcification/ ossification on serial X-rays in comparison with preoperative X-rays.
• Ectopic bone formation
• Surgical intervention related safety parameters such as but not limited to:
o Infection
o Peri- and postoperative blood loss
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 months post-surgery and follow-up at 24 months. |
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E.5.2 | Secondary end point(s) |
• Evaluation of fusion will be assessed on CT-Scans at 6, 9, 12 and 24 months post-surgery by qualitative visual analysis called the “bridging trabecular bone scale”.
• Evaluation of Non-fusion will be assessed on Dynamic Radiographs at 6, 9, 12 and 24 months post-surgery and considered as at least one of the following signs occurs: translational motion > 3 mm; angular motion > 5°; vacuum phenomenon in operated disc.
• Evaluation of bone production will be done on CT images and will be quantified by using specific software at 6, 9, 12 and 24 months post-surgery.
• Functional assessment by means of Oswestry Disability Index (ODI) at screening, 1, 6, 9, 12 and 24 months post-surgery
• Pain assessment by means of Brief Pain Inventory (BPI) at screening, pre-operation, discharge, 1, 6, 9, 12 and 24 months post-surgery
• Overall Treatment Effect scale (OTE) at 1, 6, 9, 12 and 24 months post-implant procedure.
• Quality of life assessment by means of questionnaire EuroQoL 5 Dimensions (EQ-5D-5L) at screening, 9, 12 and 24 months post-surgery
• Surgical parameters such as duration of surgery, duration of postoperative hospital stay, subsequent surgical interventions (revision, removal, reoperation and supplemental fixation).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
6, 9, 12 and 24 months post-surgery. |
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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 | Yes |
E.6.5 | Efficacy | No |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 |
Best standard of care in surgical practice |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 | No |
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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LVLS |
posledni navsteva pacienta |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |