Safety and Efficacy With NOVOCART® Disc Plus (ADCT) for the Treatment of Degenerative Disc Disease in Lumbar Spine (NDisc)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Tetec AG
ClinicalTrials.gov Identifier:
NCT01640457
First received: May 16, 2012
Last updated: October 23, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Intervertebral Disc Displacement
Intervertebral Disc Degeneration
Drug: NOVOCART® Disc plus
Drug: NOVOCART® Disc basic
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Prospective Randomized Multicentre Phase I/II Clinical Trial to Evaluate Safety and Efficacy of NOVOCART® Disc Plus Autologous Disc Chondrocyte Transplantation (ADCT) in the Treatment of Nucleotomized and Degenerative Lumbar Discs to Avoid Secondary Disease

Resource links provided by NLM:


Further study details as provided by Tetec AG:

Primary Outcome Measures:
  • Oswestry Disability Index (ODI) [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) to 12-months follow-up ] [ Designated as safety issue: No ]

    Primary efficacy variable.

    Early evaluation for efficacy will be performed when all patients completed scheduled 12-months follow-up visit (Interim analysis).


  • Oswestry Disability Index (ODI) [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) to 24-months follow-up ] [ Designated as safety issue: No ]

    Primary efficacy variable.

    Primary evaluation for efficacy will be performed when all patients completed scheduled at 24-months follow-up visit (Interim analysis).


  • Oswestry Disability Index (ODI) [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) to 60-months follow-up ] [ Designated as safety issue: No ]

    Primary efficacy variable.

    Final analysis will be performed when all patients completed scheduled 60-months follow-up visit.



Secondary Outcome Measures:
  • MRI-signal (disc height, disc volumetry, signal intensity) [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up ] [ Designated as safety issue: No ]

    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.


  • Oswestry Disability Index [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up ] [ Designated as safety issue: No ]

    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.


  • VAS for back pain and leg pain [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up ] [ Designated as safety issue: No ]

    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.


  • Health-related quality of life as measured by the SF-36 [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up ] [ Designated as safety issue: No ]

    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.


  • Healthy Questionnaire EQ-5D [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up ] [ Designated as safety issue: No ]

    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.


  • Neurological status [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up ] [ Designated as safety issue: No ]

    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.


  • Functional status [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up ] [ Designated as safety issue: No ]

    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.


  • Return to work (days) [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up ] [ Designated as safety issue: No ]

    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.


  • Analgesic Medication Use during the previous 14-day-time period [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 60-months follow-up ] [ Designated as safety issue: No ]

    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.


  • Physician assessments of ease of transplantation [ Time Frame: transplantation ] [ Designated as safety issue: No ]

    Outcome to quantify feasibility of procedure

    When all NDplus and NDbasic patients completed transplantation procedure.


  • Surgical parameters, including length of procedure [ Time Frame: Sequestrectomy and transplantation ] [ Designated as safety issue: No ]

    Outcome to quantify feasibility of procedure

    When all enrolled patients completed sequestrectomy and if applicable transplantation procedure.


  • Prevalence of subsequent surgical interventions [ Time Frame: 12-months post-operation ] [ Designated as safety issue: Yes ]

    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.


  • Any unanticipated adverse event [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy up to 60-months follow-up at any scheduled and unscheduled visit ] [ Designated as safety issue: Yes ]
    Outcome to Quantify Safety

  • Specific laboratory parameters according to product compatibility and availability: CRP, IL-6, LTE4 [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 1,5-months follow-up ] [ Designated as safety issue: Yes ]

    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


  • Histology of the tissue explant [ Time Frame: Sequestrectomy ] [ Designated as safety issue: No ]
    Outcome to Develop and Validate Biological Markers

  • Gene expression by quantitative realtime PCR of expanded cells, and cell culture medium metabolites during expansion [ Time Frame: Transplantation ] [ Designated as safety issue: No ]
    Outcome to Develop and Validate Biological Markers

  • 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) [ Time Frame: Baseline assessment 1<45d pre-sequestrectomy, pre-transplantation (90 +/- 15d post-sequestrectomy) up to 24-months follow-up ] [ Designated as safety issue: No ]
    Outcome to Develop and Validate Biological Markers


Estimated Enrollment: 120
Study Start Date: August 2012
Estimated Study Completion Date: January 2019
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: NDplus
NOVOCART® Disc plus (Autologous Disc Chondrocyte Transplantation System)
Drug: NOVOCART® Disc plus
Autologous Disc Chondrocyte Transplantation System (ADCT)
Placebo Comparator: NDbasic
NOVOCART® Disc basic (media with no active cell component)
Drug: NOVOCART® Disc basic
ADCT (Media with no active cell component)
No Intervention: Sequestrectomy only (SC)
Sequestrectomy (standard of care)

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The patient has a disc herniation with back and/or leg pain (radicular pain)
  • The patient has an indication for sequestrectomy according to the guidelines of DGNC and DGOOC (Börm, Steiger, Papavero, Herdmann, Ohmann, & Schwedtfeger, 2005)
  • The patient is skeletally mature, i.e. the epiphysial plate has to be radiologically closed.
  • The patient is between 18-60 years of age.
  • The patient is willing and able to understand the study, its goals and the possible risk factors involved.
  • The patient is sufficiently informed about this trial orally and in writing. S/he had enough time for consideration, is willing to participate in the study and gives her/his written informed consent.
  • The patient is physically and mentally able to participate in the study, including study treatment and post-surgery treatment plan.
  • The patient is willing and able to participate in the follow-up visit plan at the study the site.
  • The patient is able to understand and to comply with all recommended inclusion criteria for nucleotomy/sequestrectomy and post-op rehabilitation.
  • The patient is able to understand and to complete study-relevant questionnaires in German language.
  • The patient confirms that s/he did not participate in a clinical study 90 days prior study inclusion. S/he agrees to refrain from participating in another clinical study during the NOVOCART® Disc Study and for another 90 days after study termination.
  • Female patients must have a negative serum pregnancy test not older than 1 week prior to study entry. Female patients must be either at least two years postmenopausal or using one of the following means of birth control during the study:

    • surgical sterility
    • double barrier methods, e.g. condom or diaphragm in combination with spermicide
    • intrauterine contraceptive device
    • bilateral vasectomy of sexual partner at least 90 days prior to enrollment in combination with barrier methods (e.g. condom or diaphragm)
    • birth control pill

Radiological Inclusion Criteria

Patients enrolled in the study arm NDplus or NDbasic without adjacent degenerative disc (HD) must meet all of the following inclusion criteria.

  • The patient has a single-level lumbar disc herniation.
  • The patient has an indication for sequestrectomy according to the guidelines of DGNC and DGOOC (Börm, Steiger, Papavero, Herdmann, Ohmann, & Schwedtfeger, 2005).
  • The patient has more than 50% remaining disc height in the herniated disc in comparison to unaffected discs in the lumbar spine. If all discs show degenerative signs, disc height has to be at least 5 mm.
  • The patient has no obvious signs of osteophytes and no endplate sclerosis in the lumbar segment to be treated with NDplus or NDbasic.
  • The adjacent proximal disc has no degenerative signs according to Pfirrman Score stage 3 to 5.

Patients enrolled in the study arm NDplus or NDbasic with adjacent degenerative disc (AAD) must meet all of the following inclusion criteria.

  • The patient has a single-level lumbar disc herniation.
  • The patient has an indication for sequestrectomy according to the guidelines of DGNC and DGOOC (Börm, Steiger, Papavero, Herdmann, Ohmann, & Schwedtfeger, 2005)
  • The patient has more than 50% remaining disc height in the herniated disc in comparison to unaffected discs in the lumbar spine. If all discs show degenerative signs, disc height has to be at least 5 mm.
  • The patient has no obvious signs of osteophytes and no endplate sclerosis in the lumbar segment to be treated with NDplus or NDbasic.
  • The patients has additional degenerative signs in the proximal adjacent lumbar level according to Pfirrmann 3-4, but no more than 25% disc

Exclusion Criteria:

  • The patient has had a previous surgery at the lumbar level(s) intended for treatment with NDplus or NDbasic.
  • The patient had a past recurrent disc herniation treated with nucleotomy/sequestrectomy of the relevant disc.
  • The patient has any degenerative muscular or neurological condition that would interfere with evaluation of outcome measures including but not limited to Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy and myelopathic diseases of different causes.
  • The patient has no mobility within the lumbar spine.
  • The patient participated in a clinical trial within the last 90 days.
  • The patient is morbidly obese (BMI > 30 kg/m²).
  • The patient has current or recent history of illicit drug, nicotine or alcohol abuse, or dependence.
  • The patient has abnormal laboratory finding, e.g. persistent, increased inflammation (CRP) readings (> 10mg/dl).
  • Insufficient patient compliance: The patient is unable or unwilling to comply therapeutic instructions e.g. postoperative rehabilitation.
  • The patient is unable or unwilling to comply the follow-up visits at study site.
  • The patient is pregnant, breastfeeding or planning to become pregnant within 24 months after study entry.
  • The patient has local injections of acute or slow release corticosteroids within the last 90 days before study entry
  • The patient has a history of known allergies or a suspicion of allergies to any of the NOVOCART® Disc plus oder basic product components including hyaluronan, polyethyleneglycol or albumin.
  • The patient has a known history of HIV/AIDS.
  • The patient has a known history of Treponema pallidum (Syphilis).
  • The patient has an active hepatitis B or C infection with verified antigens. Patients with a cured hepatitis B or C infection and/or verified antibodies are not excluded.
  • Immune defects or the affinity for infections of known or unknown causes
  • The patient has a active systemic or local microbial infection, eczematization or inflammable skin alterations at the site of surgery (including Protozoonosis: Babesiosis, Trypanosomiasis (e.g. Chagas-Disease), Leishmaniasis, persistent bacterial infections, like Brucellosis, spotted and typhus fever, other Rickettsiosis, Leprosy, Recurrent Fever, Melioidosis or Tularaemia).
  • The patient is unable to undergo magnetic resonance imaging (MRI).
  • The patient has a history or a suspicion of a disease with chronically inflammable character, as rheumatoid arthritis, gout, pseudo-gout, metabolic bone diseases, Crohn's disease, ulcerative colitis, lupus erythematosus, or other autoimmune disorders.
  • The patient is considered to be at high risk for osteoporosis or osteopenia including patients who are postmenopausal, who have a high risk of osteoporosis or osteopenia (unless there is a DXA-T Score of >-1 in the past 90 days).
  • The patient has a primary hyperparathyroidism or hyperthyroidism, has chronic renal failure or has had previous fragility fractures.
  • The patient has connective tissue or collagen disease, such as scleroderma, Stickler syndrome, hypermobile syndrome, Sjögren syndrome, polymyalgia rheumatica, polymyositis, dermatomyositis, CREST-Syndrome and Sharp-Syndrome, etc.
  • Hereditary ocular degenerations with unclear diagnosis, retinopathies based on connective tissue-defined causes, macular corneal dystrophy, (based on the fact that the human cornea expresses cartilage specific proteins as essential functional elements and thus may serve as an indicator for paralleling degenerative events in various cartilaginous tissues).
  • The patient has a history of deep vein thrombosis (phlebothrombosis), including thromboembolytic disease or known thrombophilia, history or suspicion of arterial disease.
  • The patient has immune suppression.
  • The patient has a history of blood coagulation disease of different genesis, including known haemorrhagic diathesis of unknown cause.
  • The patient had undergone chemotherapy within the past 5 years, or had any cancer other than non-melanoma skin cancer treated with curative intent within the past 5 years.
  • Patient has diabetes with an HbA1c >7% before study entry.
  • The patient has a cardiac pace maker.
  • The patient has psychiatric or cognitive impairment that, in the opinion of the investigator, would interfere with the patient's ability to comply with the study requirements (e.g. Alzheimer's disease).
  • Ulterior concomitant diseases or functional impairments of specific organs, which exclude study participation by the assessment of the investigator.
  • The patient objects the saving and circulation of personal medical records according to the study protocol.
  • The patient is a prisoner.

Radiological Exclusion Criteria

  • The patient has apparent degenerative changes in the lumbar spine as determined by Modic Changes 2-3.
  • The patient has reduced disc height of more than 50% in the herniated disc in comparison to unaffected discs in the lumbar spine. If all discs show degenerative signs, disc height has to be at least 5 mm.
  • The patient with adjacent disc degeneration has reduced disc height of more than 25% in the adjacent level to be treated, as defined within the context of radiographic inclusion criteria for the adjacent level.
  • The patient has one or more dysplastic vertebral bodies within the lumbar spine.
  • The patient has a sacralized lumbar vertebra 5 at the level to be treated with NDplus or NDbasic.
  • The patient has previous or acute spondylodiscitis.
  • The patient has degenerative or lytic spondylolisthesis according to Meyerding, quantified via functional X-rays for flexion/extension in the sagittal plane.
  • The patient has isthmic spondylolisthesis, ankylosing spondylitis or spondylolysis.
  • The patient has lumbar scoliosis (> 11° sagittal plane deformity).
  • The patient has previous trauma, discography or any other surgical intervention at the lumbar spine.
  • The patient has previous compression or burst fracture at the level(s) to be treated with NDplus or NDbasic.
  • The patient has mid-sagittal stenosis of < 8mm (by MRI).
  • The patient has a spinal tumor.
  • The patient has metabolic bone disease.
  • The patient has facet ankylosis or severe facet degeneration.
  • The patient has coexistence of multiple lumbar disc herniation.
  • The patient has a lumbar kyphosis.
  • height reduction.

Intra-surgery (tissue explant/sequestrectomy) Exclusion Criteria

• Extensive damage of the Anulus, which subsequently poses a significantly greater risk of recurrence. Exceptions are discs with only minor degeneration and good chances of repair.

Exclusion Criteria prior Transplantation/Implantation

• Recurrent disc herniation after surgery and prior transplantation/implantation.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01640457

Locations
Austria
University Hospital for Neurosurgery Innsbruck
Innsbruck, Tyrol, Austria, 6020
Orthopaedic Hospital Vienna-Speising
Vienna, Austria, 1130
Germany
University Hospital Duesseldorf
Duesseldorf, Germany, 40225
Hospital "BG-Kliniken Bergmannstrost"
Halle, Germany, 06112
Berufsgenossenschaftliche Unfallklinik
Murnau, Germany, 82418
Hospital "Dr.-Horst-Schmidt-Kliniken GmbH"
Wiesbaden, Germany, 65199
Sponsors and Collaborators
Tetec AG
Investigators
Principal Investigator: Hans-Joerg Meisel, Professor Hospital "BG-Kliniken Bergmannstrost, Halle"
Principal Investigator: Claudius Thomé, Professor University Hospital for Neurosurgery Innsbruck
  More Information

No publications provided

Responsible Party: Tetec AG
ClinicalTrials.gov Identifier: NCT01640457     History of Changes
Other Study ID Numbers: AAG-G-H-1102
Study First Received: May 16, 2012
Last Updated: October 23, 2013
Health Authority: Germany: Paul-Ehrlich-Institut
Austria: Federal Office for Safety in Health Care

Keywords provided by Tetec AG:
degenerative disc
herniated disc
sequestrectomy
Autologous Disc Chondrocyte Transplantation
nucleotomy
safety
efficacy
treatment
lumbar spine
low back pain
adjacent degenerative disc
black disc
NOVOCART

Additional relevant MeSH terms:
Intervertebral Disc Degeneration
Intervertebral Disc Displacement
Spinal Diseases
Bone Diseases
Musculoskeletal Diseases
Hernia
Pathological Conditions, Anatomical

ClinicalTrials.gov processed this record on October 16, 2014