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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - NISCI (Antibodies against Nogo-A to enhance plasticity, regeneration and functional recovery after acute spinal cord injury, a multicenter European clinical proof of concept trial)

Teaser

Summary

Spinal cord injury (SCI) following work, traffic and sports accidents is a devastating neurological disorder that leaves patients with permanent paralysis. Projected to the total population of the EU of 507,4 million citizens, 10\'000 people suffer from SCI yearly and more than 200â€™000 patients are living with a SCI in the EU. Yet, no treatment is available and the impact on the individual quality of life and the economy are vast.
Todayâ€™s therapy focuses on minimizing secondary damage of the spinal cord (e.g. swelling) and subsequently rehabilitation of function at the best. The regeneration in the central nervous system (CNS) is very limited. Important molecular impediments that form the basis of this phenomenon are proteins expressed in CNS myelin, which inhibit neurite growth after CNS injury. One of the most potent neurite growth inhibitory molecules in myelin is Nogo-A, a membrane protein comprising multiple inhibitory domains that activate independent receptors. Monoclonal antibodies against Nogo-A have been shown to neutralize the inhibitory activity of purified or recombinant Nogo-A, oligodendrocytes and CNS myelin in vitro (Caroni and Schwab, 1988a, Neuron., 1:85-96; Caroni and Schwab, 1988b, J Cell Biol., 106:1281-1288). A number of publications have shown that the application of blocking anti-Nogo-A antibodies mediate significant improvements in functional recovery in rodent models of SCI (Liebscher et al 2005; Schwab & Strittmatter 2014) and primates (Freund et al., 2006), non-traumatic brain injury (Wahl et al., 2014; Wiessner et al., 2003) and traumatic brain injury (Marklund et al., 2005). These results warrant translation now to human SCI patients. A previous phase I clinical study has shown safety and feasibility in patients with complete SCI (Kucher et al., 2018). Proving the efficacy of anti-Nogo-A antibody to improve the outcome of spinal cord injured patients during a clinical phase II study is the next hurdle to be taken with the present study.
The NISCI trial also involves research studies. A biobank will collect serum and cerebrospinal fluid samples (CSF) of all NISCI patients to identify protein-based biomarkers, which may objectively measure responses to the therapeutic intervention. By novel quantitative magnetic resonance imaging (MRI) methods we try to identify microstructural changes in the spinal cord and brain.
The present study â€œAntibodies against Nogo-A to enhance plasticity, regeneration and functional recovery after acute spinal cord injuryâ€, short NISCI is an international, multi-center, double-blind, placebo-controlled trial to test the efficacy of the antibody therapy to improve motor outcome and quality of life of tetraplegic patients. Advancements in clinical trial design, improved prediction algorithms of clinical outcomes and development of surrogate markers will allow for scrutinizing the effectiveness of this novel treatment in an unprecedented way.

Work performed

Within the last year, all NISCI study documents have been established, approved by ethics committee Zurich and Swissmedic enabling an instant recruitment of patients in Switzerland. All study documents will be distributed to the EU NISCI sites as soon as all approvals in Germany has been obtained. The external scientific advisory board and the data safety monitoring board (DSMB) could be formed with international recognised scientific experts.
Training of drug handling and application, outcome and electrophysiological assessments were conducted during several local and international meetings to ensure that professionals at all sites are well-trained to follow the study protocol accordingly.
MRI protocols for high resolution and quantitative evaluation of spinal cord and brain images of patients were optimized and installed at all appropriate sites and the travelling heads study has been completed. To prepare proteomic analysis of the human cerebrospinal fluid and blood samples, and to scan for possible biomarkers of injury and repair processes, we conducted a study on spinal cord injured rats. CSF samples collected before the injury were compared by high resolution proteomic techniques to samples taken at 7 and 28 days after injury. Inflammatory markers predominated at 7 d after injury, and a series of interesting markers for repair processes, for fiber connections and circuit formation were detected at 28 days. These novel findings will guide us in the analysis of the human samples which will start to arrive in the course of 2019.
In addition, a new sensor technology targeted to the specific requirements in patients suffering from SCI has been developed and validated in several studies. This technology will enable an unobtrusive monitoring of patients trainings and abilities (Brogioli et al. 2016, Front. Neurology. ; Brogioli et al. 2016, J. Neurotrauma ; Popp et al. 2018).
The first patients to be included in the study are expected in the second quarter 2019. Additional funding has been granted to include seven new sites from the EMSCI network as associated sites to ensure faster recruitment. Those sites are funded by the charities Wings for life and Schweizer Paraplegiker Stiftung.
The NISCI website gives multi-fold information and all clinical sitesâ€™ contact data for patients. A questionnaire gives a first indication on major inclusion criteria. An information video will shortly be available.

Final results

A new statistical model tailored for the analysis of intervention studies using the upper extremity motor score (UEMS) as primary endpoint (Buri et al, 2018, submitted) aims to describe potential treatment effects as log-odds ratios. Baseline UEMS scores and neurological levels of injury are explicitly taken into account by this new model. Compared to traditional methods, such as the Wilcoxon rank sum test, the procedure has higher power for the detection of differential treatment effects.
Hospitalization and rehabilitation after spinal cord injury generate enormous both direct costs for the public health system and indirect costs due to loss of tax revenue, loss of payments into pension funds and the potential incapacity to work. As the economy of SCI is not established in the European context, we illustrate the costs by studies performed by the American Spinal Cord Injury Center. Based on these studies, the expected life time costs of a patient that suffered an injury at the age of 25 years is around US$ 2\'341\'988. Additional indirect costs which strongly depend on education, severity of injury, and preinjury employment history are estimated to an average of US$ 72\'955 per year. With an incidence rate of 10\'000 new cases per year in the EU, these costs are mammoth and a great burden to the public.
At the moment, there is no drug approved that improves the outcome in human SCI. In extensive preclinical studies, the anti-Nogo-A antibody therapy has been shown to elicit substantial functional recovery in spinal cord injured rodents and primates, which is the main prerequisite to predict efficacy in human SCI. With proof of concept the NISCI study will contribute substantially to the advancements in the field of neuroregeneration and, therewith, to the overall well-being of spinal cord injured patients. A successful proof of concept would also lay the foundation for additional clinical studies targeting other neurological disorders, such as stroke and multiple sclerosis, and the economy and patients could benefit even to a greater extent.