A prospective multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART Disc plus autologous disc chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disc to avoid secondary disease: study protocol for a randomized controlled trial

The NOVOCART™ Disc study is a nonconfirmatory, prospective, multicenter, unmasked, randomized study with two phases aimed at gathering preliminary clinical information on NOVOCART™ Disc plus and NOVOCART™ Disc basic used in the treatment of a herniated disc. Phase I aimed to develop a safety profile of the investigational medicinal product NOVOCART™ Disc plus. The objectives of phase II are mainly to provide a basis for a confirmatory clinical trial design and proof of concept. Twelve trial sites are planned to participate in this combined phase-I/II study; three of them have already participated in phase I. In total, 120 patients meeting the inclusion criteria will be randomized, treated according to the randomization, and followed up for 5 years. The primary study endpoint of the phase II is the difference in the Oswestry Disability Index (ODI) between treatment groups 2 years after the intervention. This index has emerged as the most commonly recommended condition-specific outcome measure for spinal disorders. It is a self-administered questionnaire divided into 10 sections designed to assess the limitations of various activities of daily living [11, 12]. The Short Form-36 (SF-36) questionnaire and EuroQuality of Life-5 Dimension (EQ-5D) are applied to assess changes in health status and quality of life [13, 14]. Moreover, changes in leg and back pain are assessed by the Visual Analog Scale (VAS) [15]. Numerical measurements in the disc height, volumetry, and signal intensity of index and adjacent discs and categorical evaluations, such as degeneration scale and the presence or absence of stenosis, are determined by magnetic resonance imaging (MRI). Neurological and functional status and the quantity of current pain medication and time to return to work after surgery are documented. The serology of HIV, hepatitis and Treponema palladium are determined preoperatively. Laboratory values (IL-6, Leukotriene, and CRP) as safety vales are being evaluated only in phase I of the study. Adverse events and serious adverse events are documented. Histological investigation of the explanted tissue is performed. Primary and secondary outcome parameters are outlined in more detail in Table 1.

Ethics approval was attained in Germany from the National Physician Board, “Landesärztekammer” Sachsen-Anhalt and in Austria from the committee of the Medical University Innsbruck. Furthermore, the clinical trial approval was obtained from the Paul-Ehrlich-Institute (Langen, Germany) and the Austrian Agency for Health and Food Safety (Vienna, Austria). The ethical bodies that approved the study in the various centers are listed in Table 2.

The study complies with the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects, Good Clinical Practice (GCP), national pharmaceutical acts in the participating countries (Austria and Germany), and European guidelines for the conduct of clinical trials with medicinal products for human use. The trial is initiated and sponsored by TETEC Ag (B|Braun Aesculap AG shared company, Reutlingen, Germany), which is responsible for management and registration (EudraCT No: 2010-023830-22, ID NCT01640457). CenTrial GmbH (Tuebingen, Germany) is responsible for clinical trial submission, independent clinical monitoring, and pharmacovigilance. Mediri GmbH (Heidelberg, Germany), as a core imaging lab, is responsible for the development of the MRI protocols, data storage and analyses. Laboratory values are investigated centrally by Synlab Services GmbH (Synlab MVZ, Leinfelden-Echterdingen, Germany). Accovion GmbH (Eschborn, Germany) is responsible for data management, biometrics, and medial writing. Quality assurance is being done in cooperation with participating clinical research organizations (CRO).

The N-Disc trial aims to include patients who qualify for lumbar sequestrectomy because of a lumbar disc herniation. The target population consists of patients with symptomatic lumbar disc herniation who failed adequate conservative or interventional treatment approaches in accordance with the guidelines of DGNC and DGOOC. Additionally, an MRI-determined lesion at treatment level needs to correlate with the primary symptoms. To minimize risk factors, patients with significant comorbidities have been excluded from the study. Written informed consent has been obtained from each patient. Inclusion and exclusion criteria are outlined in more detail in Table 3.

The visit plan is outlined in Fig. 1. In phase I, close monitoring of the safety parameters and additional assessment of the MRI will occur.

NOVOCART™ Disc plus (NDisc), an autologous cell compound for ADCT, was developed to provide rehydration and maintain the biological integrity of degenerative lumbar discs to prevent secondary diseases such as recurrent lumbar disc herniation, osteochondrosis, or segmental instability. NDisc plus is an injectable, in situ-polymerizing, modified albumin, hyaluronic acid gel with ex vivo-expanded autologous disc derived chondrocyte cells as the active ingredient. NDisc plus is composed of two components: Component A is a suspension with 3.6 to 4.4 million autologous intervertebral disc cells contained in a solution of modified human albumin, human serum, culture media components, chondroitin sulfate, and hyaluronic acid. The total volume is 4 ml suspension placed in a 6 ml glass vial. Component B is a bis thio-polyethylene glycol (BTPEG) solution; the total volume is 1 ml in a 2 ml glass vial. Components A and B polymerize in situ using a dedicated application system (special dual-chamber syringe) to form the desired hydrogel. The preparation is for single use during the ADCT. The dosage is individual, and the volume of injection is, depending on the capacity of the treated disc, between 0.5 and 2 ml cell suspension volume. NDisc basic is used as the placebo in the NDisc study and is the cell-free hydrogel carrier material with an identical composition but without growth factors.

Surgery is performed by two trial-designated surgeons with the assistance of an operating microscope while the patient is under general endotracheal anesthesia and in a prone position. Depending on the location of the disc herniation, the spinal canal harboring the sequestrated disc material is exposed by either a minimal interlaminar fenestration or a translaminar approach [16]. In case of a lateral lumbar disc herniation, a lateral extraforaminal approach is performed [17]. Immediately after extraction, the disc tissue is transferred into a sterile transport vial and provided to TETEC AG for the GMP compliant manufacturing of the investigational medicinal product NDisc.

The presents or absence of an adjacent degenerative disc is thought to be a potential factor affecting the prophylactic treatment capacity of NDisc plus. Analyses of primary and secondary efficacy variables will be performed separately for these two patient subgroups in addition to the overall analysis.

Transplantation is performed 90 days after sequestrectomy. N Disc plus (NDplus) or N Disc basic (NDbasic) is applied via an injection with a dual-needle technique directly at the intended site of action. NDplus or NDbasic is to be transplanted in a comfortable lateral or abdominal position. After the treatment level is localized and local anesthesia is performed, the puncture of the intervertebral disc concerned takes place contralaterally to the disc surgery. An injection needle is placed in the center of the disc space under image guidance, and the medicinal product is injected. In case of an ADD (adjacent disc degeneration), positioning of the needles and the mandrin takes place simultaneously to minimize radiation exposure (Fig. 2).

Randomization is performed intraoperatively by envelope and separately for phase I and phase II of the study. In phase I, 24 patients are randomly assigned to NDplus and NDbasic in a 1:1 allocation ratio. In phase II, 96 patients are randomly assigned to NDplus, NDbasic or follow the standard of care treatment (surgery only, SC). The allocation ratio in phase II is 2:1:1. Altogether, 60 patients will be assigned to NDplus, 36 to NDbasic, and 24 to SC (Fig. 3). Two randomization schedules are generated by CROs using Rando™ (CRO’s proprietary randomization software). The randomization schedule is kept at the CRO by the randomization code administrator, who is independent from the study team. A copy of the randomization schedule is provided to TETEC AG.

The sample size calculation is based on the primary endpoint of the study, which is the group difference in the ODI. A change of 10 units is considered as a clinically meaningful difference. Moreover, a standard deviation of 12 is assumed, based on results of a previous trial (Hägg, Fritzell, Nordwall, 2003). A sample size calculation was performed based on a two-group t-test (nQuery Advisor™ Software, version 7.0). The width of the respective confidence intervals were calculated using a large sample approximation, with 60 patients to be enrolled in the NDplus group, 36 patients in the NDbasic group, and 24 patients in the SC arm (120 patients in total). A detailed power calculation is shown in Table 4.