The PROOF project now seeks to demonstrate that NBHO (high-flow 100% oxygen at >45 L/min via a non-rebreather mask, or FiO2=1.0 for intubation/ventilation) reduces infarct growth from baseline to 24 hours compared to standard treatment if administered at 3 hours after onset of anterior circulation IS, in patients with proximal vessel occlusion and salvageable tissue at risk. The study is multi-center, adaptive phase-IIb, randomized, open-label with blinded-endpoint (PROBE design).

The primary efficacy criterion will be infarct growth from baseline to 24 hours. Secondary endpoints will be NIHSS 24h, categorical shift in the pre-stroke modified Rankin Score, QoL and cognition at day 90. Potential surrogate biomarkers, health economics and societal impacts will be assessed. If NBHO proves its neuroprotective potential in this selected population, phase-III trials in all IS patients may be undertaken. Considering its low costs and ease of use, NBHO may impact stroke care worldwide.

Population: adult | Intervention type: therapeutic medicinal product

Elderly patients have a high risk of complications after stroke, such as infections or fever. This study aims to assess whether preventive treatment in the first four days of hospitalisation with ceftriaxone, paracetamol, and/or metoclopramide prevents the most common complications and reduce the risk of death or long-term disability compared to standard care alone.

Population: adult | Intervention type: therapeutic medicinal product

PAPA-ARTIS is a phase II trial to demonstrate that a staged treatment approach can reduce paraplegia and mortality dramatically. It can be expected to have both a dramatic impact on the individual patient's quality of life if saved from a wheelchair, and also upon financial systems through savings in; 1) lower costs in EU health care; 2) lower pay-outs in disability insurance (est. at 500k in Year 1), and; 3) loss of economic output from unemployment. Approx. 2500 patients a year in Europe undergo these high risk operations with a cumulative paraplegia rate of over 15%; therefore >100M per year in costs can be avoided and significantly more considering the expected elimination of type II endoleaks.

Population: adult

This clinical trial involves two comparative analyses:

Comparison of efficacy in terms of superiority of hBM-MSCs + biomaterial (both experimental arms, low and high doses) versus iliac crest autologus graft (active comparator arm). The principal endpoint is bone consolidation at one year, defined as a combination of clinical and radiological improvements: radiological consolidation (considered as a new bone formation across the fracture site visible in 3/4 cortices, on at least 3/4 views, qualitative analysis) without pain (with and without weight bearing) and without further reoperation in the callus site.
Comparison of efficacy in terms of non-inferiority (target delta of 0.10 points) of low dose hBM-MSC+Biomaterial versus high dose of hBM-MSC+Biomaterial. The principal endpoint is the radiological consolidation, measured in a scale from 0 to 1, considering the mean consolidation of 0.6875 points (quantitative analysis).

Population: adult | Intervention type: therapeutic medicinal product

Spinal cord injury is a severe and devastating neurological disorder that leaves patients with permanent paralysis of the body. No treatment is available today to regenerate interrupted nerve fibers and repair the damaged spinal cord. The incidence of spinal cord injury is about newly injured 10’000 people per year in the EU, and due to an almost normal life expectancy more than 200’000 patients are living with a spinal cord injury in the EU. The impact on the individual quality of life is high, and social costs are enormous. Recent preclinical research in animal models succeeded to greatly enhance axonal sprouting, fiber regeneration and neuroplasticity following injuries of brain and spinal cord. These results warrant translation now to patients suffering from acute spinal cord injury. A previous phase I clinical study using intrathecal application of a nerve fiber growth promoting antibody against the growth inhibitory protein Nogo-A has shown in patients with complete spinal cord injury that this treatment is safe and well tolerated. The present study will enroll patients with various degrees of complete to incomplete acute spinal cord injury for a double-blind, placebo-controlled trial to test the efficacy of this antibody therapy to improve motor outcome and quality of life of tetraplegic patients. The enrollment of patients with different degrees of spinal cord injury is considered essential to reveal drug activity and eventual proof of concept in a broad patient population. Advancements in clinical trial design, improved prediction algorithms of clinical outcomes and development of surrogate markers (in cerebro-spinal fluid/serum and by neuroimaging) will allow for scrutinizing the effectiveness of this novel treatment in an unprecedented way. A positive outcome of this trial will represent a breakthrough for the future therapy of spinal cord injuries and beyond (traumatic brain injury, stroke, multiple sclerosis).

Population: adult | Intervention type: therapeutic medicinal product

Friedreich ataxia is a rare incurable and devastating disease. The clinical phenotype includes poor balance, impaired coordination, difficult articulation of speech and swallowing, distal weakness, deep sensory loss, visual and hearing impairment, but also heart failure, diabetes mellitus, scoliosis and foot deformities. Clinical manifestation normally starts around puberty. There is no cure or treatment that can slow down the disease which frequently results in severe disability by early adulthood. Friedreich ataxia is an inherited disorder caused by Frataxin deficiency. Nicotinamide (vitamin B3) was identified to increase Frataxin expression by an epigenetic mechanism in patients with Friedreich ataxia. This multinational study NICOFA will investigate randomized, placebo-controlled and double-blinded, whether high doses of nicotinamide are an effective treatment for Friedreich ataxia over a study period of two years. Study design and duration and number of patients to be included are based on our natural history data obtained in EFACTS (European Friedreich’s Ataxia Consortium for Translational Studies).

Population: adult & paediatric | Intervention type: therapeutic medicinal product

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease (AID) involving 0.5 to 3/1000 persons. The disease affects exocrine glands leading to dryness of the eyes and the mouth and is associated with fatigue and limb pain. In 30% to 50% of the patients, systemic and extra-glandular manifestations may develop. The spectrum of extra-glandular
manifestations in pSS is broad and includes vasculitis, peripheral neuropathy, synovitis, kidney involvement and interstitial lung disease. Moreover, pSS patients have a 10 to 20-fold higher risk of developing B cell lymphomas, conferring shorter lifetime expectancy to these patients.
Whereas 10 new targeted-immunomodulatory treatments have been marketed for rheumatoid arthritis in the past 20 years, only one drug has been licensed for other systemic AIDs, such as pSS and systemic erythematous lupus in the same period. There are several factors that may hamper the development of successful drugs for AID. Being multi-organ, these AIDs are considerably heterogeneous among individuals both in terms of clinical manifestations and biological disturbances, with, as a consequence, great difficulty to set-up accurate composite clinical end-points sensitive to change and usable in clinical trials. In this project, our objectives are:
- To develop and assess sensitive clinical endpoints, for use in future clinical trials, able to evaluate response to drug treatments in patients with pSS with high disease burden and/or systemic involvement,
- To identify and evaluate discriminative biomarkers for stratification of pSS patients predictive of organ involvement and disease progression and thus available for inclusion in clinical trials,
- To set-up and perform an original multi-arm multi-stage clinical trial to validate the newly defined pSS endpoints and the identified biomarkers, by maximizing the chance of finding a difference between the placebo arm and the treated arm.

Population: adult | Intervention type: therapeutic medicinal product

The major objective is to develop novel clinical endpoints for clinical trials with a regulatory and patient access intention in patients with intermediate age-related macular degeneration (iAMD). Additional objectives are to characterise visual impairment in iAMD and its progression, as well as identify risk factors for progression to late stage AMD.

Population: adult | Intervention type: non-interventional study

The objective of the LIVERHOPE project is to evaluate a novel therapeutic strategy for patients with cirrhosis based on a combination of rifaximin and simvastatin, targeting the main pathophysiological mechanisms of disease progression , namely the impairment in the gut-liver axis and the persistent hepatic and systemic inflammatory response. This dual therapeutic approach is supported by preclinical data showing excellent and very promising results.
LIVERHOPE will include two randomized double-blind trials (LIVERHOPE SAFETY and LIVERSHOPE EFFICACY) to investigate safety, tolerability and efficacy of combination of simvastatin plus rifaximin in patients with decompensated cirrhosis in six EU countries (285 patients will be enrolled in two trials in Germany, France, Italy, Spain, The Netherlands, and the United Kingdom). The expected impact is to halt progression to acute-on-chronic liver failure, the main cause of death, to decrease complications of the disease, to reduce hospital re-admissions, to improve cost-effectiveness of therapy.
The aim of the LIVERHOPE SAFETY trial is to assess the safety and tolerability of oral administration of simvastatin plus rifaximin in patients with decompensated cirrhosis.
The aim of LIVERHOPE EFFICACY is to assess the efficacy of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis to prevent ACLF development.

Population: adult | Intervention type: therapeutic medicinal product

The aim of this trial is to determine preliminary activity of the combination treatment with nivolumab and entinostat in children and adolescents with high risk refractory/relapsed/progressive tumors harboring a high mutational load, high PD-L1 mRNA expression or focal MYC(N) amplification and explore activity in biomarker low tumors (low mutational load, low PD-L1 mRNA expression and non-MYC(N) amplified).

Population: paediatric | Intervention type: therapeutic medicinal product