The Daily Telegraph heralds a new drug that “could reduce the risk of stroke in thousands of patients undergoing brain operations”.
This is based on a randomised controlled trial of a new drug called NA-1.
The study looked at 185 adults who were having a type of surgery called endovascular coiling to treat a brain aneurysm. A brain aneurysm is a bulge in a blood vessel that’s caused by a weakness in the blood vessel wall. Surgery is often recommended for larger aneurysms as there is a risk they might rupture (burst open), which can cause devastating bleeding inside the brain.
Endovascular coiling can also be used to fix aneurysms which have ruptured.
While endovascular coiling has proved effective, it carries a high risk of causing blood clots to develop in the blood vessels of the brain, triggering a stroke and damaging brain tissue. The researchers estimated that 90% of people treated with coiling experience a stroke, which are often so small, they can only be detected using a brain scan.
In many cases, the strokes are minor and cause no significant side effects. However, in a minority of cases the strokes can be severe and lead to extensive brain damage and a corresponding decline in cognitive function.
The current study found that people who received NA-1 after their surgery were less likely to develop areas of damaged brain tissue than those who received a “dummy” injection.
The new drug NA-1 shows promise in this small, early stage trial. Larger trials will be needed before it could be approved for use in clinical practice.
Where did the story come from?
The study was carried out by researchers from the University of Calgary in Canada and other research centres in Canada and the US. It was funded by NoNO Inc, the company that developed the drug being tested, and Arbor Vita Corp, another drug development company. The study was published in the peer-reviewed medical journal, The Lancet Neurology.
The Telegraph and BBC News covered this story appropriately, describing the promise of the treatment, but also including quotes noting the need for further research.
What kind of research was this?
This was a phase II randomised controlled trial assessing whether a new drug called NA-1 was safe and could treat the type of brain damage seen in stroke.
The researchers say that there is a major need to develop drugs that can protect the brain from the damage that occurs when its oxygen supply is reduced, or cut off, such as in a type of stroke called ischaemic stroke. They say that over 1,000 treatments that have shown promise in animal models for this use have not translated into successful human drugs.
NA-1 belongs to a new and exciting class of drugs known as PSD95 inhibitors. When the oxygen supply to the brain is blocked, as is the case during a stroke, a complex series of biochemical reactions occur which result in the damage or death of brain cells. PSD95 inhibitors, such as NA-1, can disrupt one aspect of these reactions., helping to preserve brain tissue. Researchers hope that this will help to prevent the death of brain tissue.
The drug has shown promise in animal testing for reducing the area of brain damage resulting from stroke, and phase I testing in healthy humans has identified an appropriate dose for human use that did not cause serious adverse effects. The current study aimed to assess the drug’s safety, and other effects, in humans having surgery to repair a blood vessel in the brain. Small blood clots can form during this procedure, and these may block small blood vessels in the brain, leading to small areas of the sort of brain damage seen in stroke. These small areas of damage may not cause as severe disabling effects as a full stroke, but may affect cognitive functions, such as memory and language skills.
The researchers wanted to see whether NA-1 could help prevent this type of damage.
What did the research involve?
The researchers recruited 197 adults who needed to have brain surgery to repair a blood vessel that had ruptured (burst), or was in danger of bursting. They only included people whose repair could be carried out by minimally invasive surgery, using a technique called endovascular intracranial aneurysm repair (often referred to as endovascular coiling). Twelve participants were eventually excluded from the study as they did not meet the inclusion criteria.
The participants were randomly assigned to receive either an intravenous infusion of the new drug NA-1, or a placebo solution after completion of the repair, but before they came out from their general anaesthetic. The pharmacists who prepared the drug infusion knew which treatment was being received, but neither the participants nor the doctors assessing them knew which solution had been used (the study was double blind). This stops the views of the participants and doctors about potential effects of the drug from influencing the results.
The participants had an MRI brain scan before their surgery, and then again 12–96 hours after drug infusion. The researchers looked at the MRIs for new areas where the brain tissue was damaged because it had been starved of oxygen, which were not there before the surgery. They also looked at the size of these areas of damage (called lesions).
The participants were also assessed clinically by doctors immediately after surgery, and at two to four days and 30 days after the surgery. As participants who had a ruptured blood vessel would be expected to have more severe brain damage than those whose blood vessels were only in danger of bursting, they only had brain function testing at day 30.
The researchers compared the outcomes of participants who received NA-1 and those who did not, including whether they had any adverse effects.
What were the basic results?
About two-thirds of participants were found to have developed new areas of brain damage (lesions) after their surgery. The researchers found that participants who received NA-1 had about 41-47% fewer new lesions compared with participants who received placebo. Participants receiving NA-1 had an average of three to four new lesions (depending on the method used to assess the lesions), while participants receiving placebo had an average of about five to seven new lesions.
The researchers found no difference in the volume of the areas of damage in the brains of participants treated with NA-1 or placebo, or in clinical outcome of the patients overall.
No serious adverse events were identified as being related to treatment with NA-1. Two participants developed transient low blood pressure while receiving NA-1 treatment, these were judged to be mild events and resolved within a few minutes. Two participants in the NA-1 group had large strokes after their surgery, these strokes were judged to be related to the surgery itself and not to NA-1.
How did the researchers interpret the results?
The researchers concluded that their results show that it is possible to protect the brain from the damage caused by oxygen starvation. They say that larger trials are needed to investigate the effects of NA-1 further.
This small trial has shown that the new drug NA-1 shows promise for reducing the risk of brain damage after minimally invasive surgery for blood vessel repair in the brain. The study had a good design, and its results seem likely to be promising enough for the drug to continue to be studied in larger phase III trials. This additional research will be needed to:
- confirm the results seen in this trial
- assess longer term outcomes of the participants
- more closely assess whether NA-1 has any effect on the patients’ brain function, their overall function, and their quality of life
further assess the potential for less common adverse effects with NA-1 in a larger group of people
- assess whether NA-1 has similar effects in people with other conditions involving areas of brain damage due to oxygen starvation, not just those undergoing brain surgery.
This additional research will take time, and continued positive results will be needed before the drug regulators can give it authorisation for use in clinical practice.
Developing drugs that can protect the brain is challenging, and it is hoped that research such as this will eventually result in more ways to help people suffering the effects of stroke and related brain damage.
- Hill MD, Martin RH, Mikulis D, et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. The Lancet Neurology. Published online October 8 2012