A multi-centre, double-blinded, randomised trial, led by a team at the Cumming School of Medicine (CSM) Hotchkiss Brain Institute and Alberta Health Services, investigates the use of the neuroprotective drug nerinetide, developed by NoNO Inc, in two scenarios in the same trial.
In one scenario, nerinetide is given to patients in addition to the clot-busting drug alteplase. In the second scenario, patients who were not suitable for alteplase received only nerinetide. Both groups of patients had concurrent endovascular treatment (EVT) to remove the clot.
"Compared to placebo, almost 20 per cent more patients who received nerinetide along with endovascular treatment, but did not receive alteplase, recovered from a devastating stroke – a difference between paralysis and walking out of the hospital," says Dr Michael Hill, a neurologist at Foothills Medical Centre (FMC) and professor in the departments of clinical neurosciences and radiology at the CSM. "In the patients who received both drugs, the alteplase negated the benefits of the nerinetide."
Hill says the study provides evidence of a biological pathway that protects brain cells from dying when they are deprived of blood flow. Nerinetide targets the final stage of the brain cell's life by stopping the production of nitric oxide within the cell.
"We really believe this is a new scientific observation," says Hill. "There is evidence nerinetide promotes brain cell survival, offering neuroprotection until we can extract the clot. It opens the door to a new way of treating stroke."
Images of patients' brains from the study show the expected size of the damage from the stroke is sizeably reduced when nerinetide is administered and EVT is performed among patients not concurrently receiving alteplase.
"After so many studies investigating neuroprotective drugs failed, we are extremely excited by these results," says Dr Mayank Goyal, a neuroradiologist at the FMC, and clinical professor in the department of radiology at the CSM. "While nerinetide is not approved for use yet, it shows the potential of a new tool to promote recovery from stroke."
Worldwide, 15m people suffer a stroke each year – that's one every nine minutes in Canada and every 90 seconds in the US. The results can be devastating. Ischemic stroke, the most common, is caused by a clot in a blood vessel in the brain. The sudden loss of blood flow causes brain cells to die, which can permanently affect speech, vision, balance and movement.
The international trial enrolled 1,105 patients between March 2017 and August 2019 at centres in North America, Europe, Australia, and Asia – a global academic collaboration bringing together scientists, clinicians, funding agencies, and industry.
"The collaboration between NoNO Inc, the University of Calgary and investigators at 48 leading stroke hospitals around the world has shown how effective such an academic-industry partnership can be in running high-quality, foundational stroke trials that can lead to positive changes in clinical practice," says Dr Michael Tymianski, CEO of NoNO Inc and the inventor of nerinetide.
The results in the current study, called the ESCAPE-NA1 Trial, build on the success of the ESCAPE trial, in which the Calgary Stroke Programme proved that a clot retrieval procedure known as EVT can dramatically improve patient outcomes after an acute ischemic stroke. During the procedure, a catheter is inserted in the groin and guided through blood vessels into the brain. A tiny metal mesh device is used to grab the clot and pull it out. The current study investigates whether administering nerinetide in addition to clot retrieval improves the patient's ability to recover.
The study is supported by the Canadian Institutes of Health Research (CIHR), Alberta Innovates, and NoNO Inc. Hill is a member of the scientific advisory board for NoNO Inc It is an unpaid position and he receives no financial benefit from the results.
Abstract
Background: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke.
Methods: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0–2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0–1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018.
Findings: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0–2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96–1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups.
Interpretation: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo.
Funding: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.
Authors
Michael D Hill, Mayank Goyal, Bijoy K Menon, Raul G Nogueira, Ryan A McTaggart, Andrew M Demchuk, Alexandre Y Poppe, Brian H Buck, Thalia S Field, Dar Dowlatshahi, Brian A van Adel, Richard H Swartz, Ruchir A Shah, Eric Sauvageau, Charlotte Zerna, Johanna M Ospel, Manish Joshi, Mohammed A Almekhlafi, Karla J Ryckborst, Mark W Lowerison, Kathy Heard, David Garman, Diogo Haussen, Shawna M Cutting, Shelagh B Coutts, Daniel Roy, Jeremy L Rempel, Axel CR Rohr, Daniela Iancu, Demetrios J Sahlas, Amy YX Yu, Thomas G Devlin, Ricardo A Hanel, Volker Puetz, Frank L Silver, Bruce CV Campbell, René Chapot, Jeanne Teitelbaum, Jennifer L Mandzia, Timothy J Kleinig, David Turkel-Parrella, Donald Heck, Michael E Kelly, Aditya Bharatha, Oh Young Bang, Ashutosh Jadhav, Rishi Gupta, Donald F Frei, Jason W Tarpley, Cameron G McDougall, Staffan Holmin, Joung-Ho Rha, Ajit S Puri, Marie-Christine Camden, Götz Thomalla, Hana Choe, Stephen J Phillips, Joseph L Schindler, John Thornton, Simon Nagel, Ji Hoe Heo, Sung-Il Sohn, Marios-Nikos Psychogios, Ronald F Budzik, Sidney Starkman, Coleman O Martin, Paul A Burns, Seán Murphy, George A Lopez, Joey English, Michael Tymianski
[link url="https://news.ucalgary.ca/news/research-shows-new-drug-helps-preserve-brain-cells-time-after-stroke"]University of Calgary material[/link]
[link url="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30258-0/fulltext"]The Lancet abstract[/link]