NOVOCART® Disc plus is being investigated to explore its clinical applicability, safety and efficacy in the repair of a herniated disc with an indication for an elective sequestrectomy, and of the adjacent degenerated disc, if present. The objective of this clinical study is to provide basis for a confirmatory study design (endpoints, methodologies) (Phase II), and to develop a safety profile (Phase I). This study further aims at developing and validating known and new biologic markers for the quality and clinical efficacy of the product as requested in the context of identity, purity and potency characteristics of the medicinal/investigational product.
This is a classical Phase II study with an implicated Phase I part. The Phase I/II combination study is a non-confirmatory study aimed at gathering preliminary clinical information on NOVOCART® Disc plus used in a new indication in the repair of a herniated disc. It will be conducted in a prospective, multicenter, unmasked, clinical trial including 120 subjects randomized to NOVOCART® Disc plus (NDplus, 60 subjects), media NOVOCART® Disc basic with no active cell component (NDbasic, 36 subjects) and to standard of care (SC) sequestrectomy as control (24 subjects). 24 patients will be enrolled in Phase I of the study (12 NDplus, 12 NDbasic) and 96 patients in Phase II (48 NDplus, 24 NDbasic, 24 SC). All subjects will be evaluated at 1.5-, 3-, 6-, 12-, 24-, 36-, 48-months post-t0 examination in the SC study arm and 1.5-, 3-, 6-, 12-, 24-, 36-, 48-months post-t5 examination in the NDplus and NDbasic study arms, and then 5 years post-t0/t5 to collect long-term clinical data. Efficacy measurements for functional improvement will be evaluated among NDplus, NDbasic and SC. Physiological effects observed from MRI measurements will be compared between appropriate treatments depending on expected treatment mechanisms. Safety data of NDplus will be combined with NDbasic to contrast against SC on procedure related risks and NDplus against NDbasic and SC together on graft-related adverse experiences. To optimize the usefulness of clinical information, data collected in the study may be analyzed and reviewed continuously. Early findings may be used to modify the study design when deemed appropriate and acceptable by the Sponsor's medical advisors. Data-driven adaptive actions include but are not limited to stopping enrollment early. The Sponsor will inform regulatory bodies, Ethic Committees, and investigators before implementing study design modifications. Cells and tissues collected from this study will be used in other in vitro-controlled experiments aimed at developing and validating known and novel biologic markers to quantify cell quality in the context of identity, purity and potency. Prognostic values of these biologic markers will be examined by correlating them with clinical data collected in this study. The study will follow each subject for a total of five years post-t0 examination in the SC study arm and post-t5 examination in the NDplus and NDbasic study arms to obtain long-term performance data. Patients must have a single-level acute disc herniation with an indication for an elective sequestrectomy. They may further have corresponding disc degeneration in the proximal adjacent segment (Pfirrmann Score Stage 3-4). A total of 120 adults will be enrolled in this study. Each patient will remain in the study for 5 years post t0/t5 examination to complete the planned follow-up phase. It is expected to take 6 years and five months to collect all required data for this study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
120
Autologous Disc Chondrocyte Transplantation System (ADCT)
ADCT (Media with no active cell component)
University Hospital for Neurosurgery Innsbruck
Innsbruck, Tyrol, Austria
Charité Universitätsmedizin
Berlin, Germany
DRK Kliniken Berlin Westend
Berlin, Germany
University Hospital Duesseldorf
Düsseldorf, Germany
Universitätsmedizin
Göttingen, Germany
Hospital "BG-Kliniken Bergmannstrost"
Halle, Germany
SHG Klinikum
Idar-Oberstein, Germany
Städtisches Klinikum
Karlsruhe, Germany
Berufsgenossenschaftliche Unfallklinik
Murnau am Staffelsee, Germany
St. Franziskus Hospital
Münster, Germany
Oswestry Disability Index (ODI)
Primary efficacy variable. Early evaluation for efficacy will be performed when all patients completed scheduled 12-months follow-up visit (Interim analysis).
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) to 12-months follow-up
Oswestry Disability Index (ODI)
Primary efficacy variable. Primary evaluation for efficacy will be performed when all patients completed scheduled at 24-months follow-up visit (Interim analysis).
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) to 24-months follow-up
Oswestry Disability Index (ODI)
Primary efficacy variable. Final analysis will be performed when all patients completed scheduled 60-months follow-up visit.
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) to 60-months follow-up
MRI-signal (disc height, disc volumetry, signal intensity)
Secondary efficacy variable Early evaluation for efficacy will be performed at 12-months follow-up, primary evaluation for efficacy will be performed at 24-months follow-up, and final analysis will be performed at 60-months follow-up.
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up
Oswestry Disability Index
Secondary efficacy variable Early evaluation for efficacy will be performed at 12-months follow-up, primary evaluation for efficacy will be performed at 24-months follow-up, and final analysis will be performed at 60-months follow-up.
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up
VAS for back pain and leg pain
Secondary efficacy variable Early evaluation for efficacy will be performed at 12-months follow-up, primary evaluation for efficacy will be performed at 24-months follow-up, and final analysis will be performed at 60-months follow-up.
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up
Health-related quality of life as measured by the SF-36
Secondary efficacy variable Early evaluation for efficacy will be performed at 12-months follow-up, primary evaluation for efficacy will be performed at 24-months follow-up, and final analysis will be performed at 60-months follow-up.
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up
Healthy Questionnaire EQ-5D
Secondary efficacy variable Early evaluation for efficacy will be performed at 12-months follow-up, primary evaluation for efficacy will be performed at 24-months follow-up, and final analysis will be performed at 60-months follow-up.
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up
Neurological status
Secondary efficacy variable Early evaluation for efficacy will be performed at 12-months follow-up, primary evaluation for efficacy will be performed at 24-months follow-up, and final analysis will be performed at 60-months follow-up.
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up
Functional status
Secondary efficacy variable Early evaluation for efficacy will be performed at 12-months follow-up, primary evaluation for efficacy will be performed at 24-months follow-up, and final analysis will be performed at 60-months follow-up.
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up
Return to work (days)
Secondary efficacy variable Early evaluation for efficacy will be performed at 12-months follow-up, primary evaluation for efficacy will be performed at 24-months follow-up, and final analysis will be performed at 60-months follow-up.
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up
Analgesic Medication Use during the previous 14-day-time period
Secondary efficacy variable Early evaluation for efficacy will be performed at 12-months follow-up, primary evaluation for efficacy will be performed at 24-months follow-up, and final analysis will be performed at 60-months follow-up.
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up
Physician assessments of ease of transplantation
Outcome to quantify feasibility of procedure When all NDplus and NDbasic patients completed transplantation procedure.
Time frame: transplantation
Surgical parameters, including length of procedure
Outcome to quantify feasibility of procedure When all enrolled patients completed sequestrectomy and if applicable transplantation procedure.
Time frame: Sequestrectomy and transplantation
Prevalence of subsequent surgical interventions
Outcome to Quantify Safety A subsequent surgical intervention is defined as any invasive procedure performed at the index level to treat the same condition (herniation) or other conditions resulted from the transplantation/implantation procedure within the 12-month period post-operation.
Time frame: 12-months post-operation
Any unanticipated adverse event
Outcome to Quantify Safety
Time frame: Baseline assessment 1<45d pre-sequestrectomy up to 60-months follow-up at any scheduled and unscheduled visit
Specific laboratory parameters according to product compatibility and availability: CRP, IL-6, LTE4
Outcome to Quantify Safety (Phase I only) At sequestrectomy, 2h-, 6h-, 24h-, 36h- post surgery, transplantation, direct after transplantation, 6h-, 12h-, 18h-, 24h-, 30h-, 36h-, 42h-, 48h- post transplantation, 3 and 6 weeks post transplantation
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 1,5-months follow-up
Histology of the tissue explant
Outcome to Develop and Validate Biological Markers
Time frame: Sequestrectomy
Gene expression by quantitative realtime PCR of expanded cells, and cell culture medium metabolites during expansion
Outcome to Develop and Validate Biological Markers
Time frame: Transplantation
Biomarkers of blood and urine samples (SOX9, MMP-3, collagen type I, collagen type II, collagen type X, IL-1, aggrecan, BMP receptor Ia, BSP-2, FLT-1, collagen crosslinks, and yet to be defined additional elements)
Outcome to Develop and Validate Biological Markers
Time frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 24-months follow-up
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