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Antibodies against Nogo-A to enhance plasticity, regeneration and functional recovery after acute spinal cord injury, a multicenter European clinical proof of concept trial

Periodic Reporting for period 3 - 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)

Reporting period: 2019-01-01 to 2020-06-30

Spinal cord injury 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 spinal cord injury yearly and more than 200’000 patients are living with a spinal cord injury in the EU. Yet, no treatment is available and the impact on the individual quality of life and the economy are vast.
Today’s therapy focuses on minimizing secondary damage of the spinal cord (e.g. swelling) and on subsequent rehabilitation of function at best. Regeneration of interrupted nerve fiber tracts in the central nervous system is very limited. Important molecular impediments responsible for this lack of fiber repair are proteins which inhibit nerve fiber growth after brain or spinal cord injury. One of the most potent nerve growth inhibitory molecules is Nogo-A, a membrane protein comprising multiple inhibitory domains that activate independent receptors. Function blocking antibodies against Nogo-A neutralize this inhibitory activity and allow injured nerve fibers to regrow and reconnect. A number of publications have shown that such anti-Nogo-A antibodies mediate significant improvements in functional recovery in rats, mice and monkeys with spinal cord injuries. These results warranted translation to human spinal cord injured patients. A previous phase I clinical study has shown safety and feasibility in patients with complete injuries (Kucher et al., 2018). Testing the efficacy of anti-Nogo-A antibody to improve the outcome of spinal cord injured patients during a clinical phase II study is therefore the objective of the present study. The present study “Antibodies against Nogo-A to enhance plasticity, regeneration and functional recovery after acute spinal cord injury”, short NISCI, is an international, multi-center, double-blind, placebo-controlled trial to test the efficacy of the anti-Nogo-A 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. The NISCI trial also involves research studies. A biobank is collecting 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.
Within the last year, all NISCI study protocols and all the drug and trial related documents were completed and approved by ethics committees and the Regulatory Authorities in Switzerland, Germany, Spain and Czech Republic. Recruitment of patients has started in Germany and Switzerland. Sites in Spain, Italy and the Czech Republic are in the process of being activated within in the next few weeks. The external scientific advisory board and the data safety monitoring board (DSMB) will meet after inclusion of the 30th patient.
Training of drug handling and application, outcome and electrophysiological assessments were conducted during several webinars, phone contacts 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. Cerebrospinal fluid 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 days 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 has been started recently.
In addition, a new limb movement sensor targeted to the specific requirements of tetraplegic patients has been developed and validated in several studies. This technology will enable unobtrusive monitoring of patient's trainings and abilities.
The first patients were included in the study in the third quarter 2019. During the last 10 months, 29 patients have been successfully enrolled. In addition to the EU funding, substantial funding by two private foundations, Wings for Life (Austria) and Schweizer Paraplegiker Stiftung (Switzerland) has been granted to include seven additional sites to ensure timely recruitment.
The NISCI website provides multi-fold information on the clinical trial including contact information regarding participating clinical sites for patients and a questionnaire for an eligibility self-test. In two project videos, the clinical trial and its scientific background are presented.
At the moment, there is no drug approved that improves the outcome after a severe spinal cord injury. 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 humans. Showing proof-of-concept for an anti-Nogo-A therapy in tetraplegic patients, 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.
A new statistical model tailored for the analysis of intervention studies using the upper extremity motor score as primary endpoint (Buri et al, 2020, BMC Medical Research Methodology) establishes the description of potential treatment effects as log-odds ratios. Baseline upper extremity motor 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 inability to contribute to the work force. As the economy of spinal cord injury is not established in the European context, we illustrate the costs by studies performed in the US. There, the expected lifetime costs of a patient who suffered an injury at the age of 25 years is around US$ 2'342'000. Additional indirect costs that 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 major burden to the public.