Associate professor of neurology, Division of Neuromuscular Medicine, and director, Neuromuscular Clinical Trials, Columbia University 

Jinsy A. Andrews, MD, MSc

Jeremy, I have heard about a drug called arimoclomol. What can you tell us about that?

Arimoclomol has probably been around the ALS [amyotrophic lateral sclerosis] community for 15 years. It is a drug that was evaluated in preclinical models first and is a coinducer of a heat shock protein called Hsp70. Heat shock proteins are chaperones that help remove toxic elements from a cell. More research has been done on arimoclomol preclinically, and it clearly has a direct effect on lysosomal activity, and it enhances the ability of lysosomes and cells to clear protein aggregates. It was studied in a study of 100 patients. It was a 3-month study, and it was shown to be well tolerated and have good CNS [central nervous system] penetrance.

It was then studied in a group of patients with familial ALS with SOD1 mutations. Although that was a small study, there was a suggestion that it was positive in that group. It has then been studied in a variety of storage diseases including a disease called Niemann-Pick. A phase 3 study of Niemann-Pick was reported as positive, and the drug is being considered by the FDA for approval in that regard. In the context of a relatively large, relatively long placebo-controlled trial, arimoclomol is close to completion in ALS. I do not know the dates, but it is likely to be sometime this quarter or next when we will get the results, and we will find out whether it has a role.

 Thank you. Ammar, the next on our list of tongue twisting medications is masitinib.

Masitinib was part of a remarkably complex study design. It was a phase 2b/3 study. It transitioned seamlessly from phase 2 to 3. Masitinib itself is a tyrosine kinase inhibitor. It modulates mast cells and macrophages, and it and is thought to have neuroinhibitory, neuroprotective properties. The study randomized 394 people 1:1:1 of placebo with riluzole, masitinib at 3 mg/kg per day with riluzole, or masitinib 4.5 mg/kg per day with riluzole. In other words, everyone was given riluzole, and people were either given placebo or low-dose or high-dose masitinib. 

That was the basic dosing regimen, but that was superimposed on top of another stratification of patients. Patients were assessed for their ALS FRS [Functional Rating System] rate of decline and classified as normal progressors, which was defined as a rate of decline of 1.1 points or less per month, or fast progressors. They then ended up with people who were normal progressors on either of the 2 dose types or placebo. They then grouped normal progressors and fast progressors as the other group. It was not normal or fast; it was normal and fast as the comparator arm on the 3 different arms. It was an incredibly complex study design, which is part of the reason it has been difficult for the community to understand the results. 

The main result was that, for the people who were normal progressors and had a high dose, there was a significant difference in the rate of disease progression. There was an improvement in the rate of disease progression compared with the other arms, but the difficulty was that, even though these were prespecified by the study team as analyses, it was regarded as multiple testing and just trying every single thing in the hope that 1 would come out positive, which is not necessarily a fair interpretation of it. 

That is part of the difficulty is that this is a complex study design. The idea would be to go back and do the phase 3 study with a simpler study design and try with the normal progressors at a high dose and see what that shows. 

Jeremy, this past summer, in the New England Journal of Medicine, we saw the results of our first gene therapy trial in ALS. It was of a drug called tofersen. Can you tell us about that?

Tofersen is an antisense oligonucleotide, meaning it is a string of nucleic acids that was actually engineered to match a string of nucleotides that exist in the SOD1 gene. The purpose of this is that the antisense binds to the gene, inhibits production, and potentially even then provides a substrate for which the gene and the antisense together can be degraded. It was shown to reduce the amount of SOD1 protein successfully, whether mutant or normal, in experimental animals and in human subjects with ALS.

What was reported in the New England Journal of Medicine study was a seamless phase 1/2, phase 2 study where patients were initially given low doses of tofersen and then somewhat higher doses. The number of subjects at the higher dose was somewhat enriched so that they had a small number of patients there, but they potentially had enough to look at efficacy variables. They were now looking at patients with SOD1 who were rapidly progressive. Even over 3 months, you expect these patients to decline quite dramatically. 

The patients who were on the higher dose of tofersen, who were rapidly progressive, essentially progressed not at all for those 3 months. Even though it was a short study and even though it was a small number of people, that difference is apparently dramatic and suggests that this could be a dramatically effective treatment for patients with this form of ALS. An ongoing study is testing that same higher dose in a larger number of people to make sure that this is not a fortuitous finding.

One of the findings that also suggested this is potentially real is that a biomarker of axon degeneration on neurofilament light chain also was clearly reduced in patients taking tofersen. Neurofilament light chain is reliably increased in patients with ALS. Overall, this is quite encouraging.

 That sounds very exciting. Jinsy, how about ibudilast?

I will talk quickly about ibudilast, which is also referred to as MN-166, which is an investigational product. It is still in clinical trials. Ibudilast is an anti-inflammatory drug. It is a phosphodiesterase inhibitor, but it also inhibits the macrophage migration inhibitory factor. It is meant to be neuroprotective by helping to protect the motor neurons and prevent degeneration. It has already completed early phase clinical trials. It demonstrated a decent safety and tolerability, but the question now is its effectiveness. In the United States, and I believe there are sites in Canada as well, the clinical trial has launched and is actively recruiting for participants in a 12-month study. The randomization is 1:1 placebo or treatment. After that 12-month duration, the open-label extension will continue to be offered to the participants who complete that 12 months placebo-controlled study. The study is recruiting, and we are awaiting results.

This was a very exciting section. If I could look into a crystal ball and think about what the future in ALS might look like, there may come a day when we can pick off individual patients based on the specific cause of their disease. We could say there is 1 specific gene that we can go after and maybe stop the progression in that small percentage of patients. For everybody else, we may have a cocktail of medications that hit different downstream mechanisms, which is so-called rational polypharmacy. It is exciting to think about that. 

Let me ask 1 last question. I am going to ask this to each of you: If you could give 1 piece of advice to a community neurologist who is seeing a patient with ALS, what would it be? Jinsy?

I would ask for our community neurologists to know that ALS should not be said in the same sentence as “death sentence.” There is something that we can do for these patients, so they must try to identify these patients earlier and get them to an ALS center as quickly as possible.

Mine would be to think of ALS because, for the reasons everyone has discussed already, it can be difficult to think of. As Jinsy says, do not destroy hope. It is important to refer early and not destroy hope.

 I will sound like a broken record, but I completely agree that it is important not to destroy the person’s view of a life that is worth something and that ALS is best cared for in a multidisciplinary clinic. If there is 1 available in your area, please think about referral.

 I appreciate spending this time with the 3 of you. I do not know if I have ever gotten this much of your time before, but I have learned a lot from all of you today. To our audience, thank you for watching this NeurologyLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box.

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Key opinion leaders review the study design and mechanisms of action for drugs in ongoing clinical trials and consider the future of amyotrophic lateral sclerosis (ALS). 

Ongoing Clinical Trials and the Future of ALS 

 I am smiling as I look at this next question on our agenda because I know we could easily spend hours on this. All of you are thought leaders and are passionate about clinical trials. I am going to ask you each to tell me 1 thing that excites you about the way we are doing ALS [amyotrophic lateral sclerosis] clinical trials now compared with 10 years ago. Ammar, I will start with you.

The most exciting thing is that we are working collaboratively with a specific aim that was not there many years ago, which is that we learn from every single trial. Regardless of whether the drug shows efficacy, we have learned something about ALS from that trial. Whether it is that biomarkers change and what the biomarker might be, or whether it is that gene variants affect prognosis, there is no trial that is giving us that information. 

That is important because patients and their families are giving huge amounts of time and effort into going into a trial. If the trial does not show a benefit at the end, then that is not respecting the time that they have given. If we are learning something, regardless of whether the drug itself works, even if it is a disappointing result, and we do not have a drug that works, then it at least means that we have learned something that we can take back to improve and do the next trial better because we have that extra information.

 I will be quick and say 2 things. One is that our expanding knowledge of the pathophysiology of ALS has led to a whole host of new targets that we can now assess whether we are influencing. As Ammar said, given that we can assess that, we can make a determination of whether that specific intervention has promise in ALS. I would then say that, not necessarily for phase 3 trials but for middle phase trials, the development of both fluid and other kinds of biomarkers gives us the potential to see drug- and disease-related activity based on your drug in a much shorter period of time with a smaller number of patients. We have the potential to speed up clinical development based on those 2 aspects. 

I do not have much more add except for the fact that what both Ammar and Jeremy pointed out lend lends itself to being innovative in the trial design itself. Using biomarkers to enrich the population that you would evaluate for a particular therapy because it is pertinent of the target might make us more successful in clinical trials by using clinical trial design to evaluate multiple drugs quickly. That is the basis behind what we call platform trials, which is an infrastructure that is set up both in Europe and also in the United States to evaluate drugs efficiently and quickly while being respectful of a participant’s time and altruism for their participation in the clinical trial.

Thinking innovatively about adaptive trial designs as well, we are at a time with ALS where all these components interplay with one another: collaborating, studying outcomes, studying biomarkers, and implementing them in trial design makes sure that we get to an answer more quickly. 

 I cannot help but answer this question myself as well. For me, it is patient engagement. In the past decade, we have seen patients transform from just subjects in our studies to partners. We now have a massive group of patients and families who are trained to understand research, and we are networking with them on a regular basis to get them more involved. 

They are helping us raise money. They are helping us change laws to get more studies. They are helping us ask more relevant questions. They are helping us with trial designs that are more attractive, where people are not going to drop out in such high numbers. They are helping us spread the word. They are helping sponsors craft a message about the results that the community understands. They are working with regulators like the FDA so they have a better understanding of what benefit-risk ratios look like from a patient’s perspective. That is my answer to that one. 

Let’s now shift our attention and talk a bit about some drugs in development. Jinsy, what can you tell us about AMX0035?

AMX0035 is an investigational product being evaluated in ALS. It recently completed a clinical trial. It is a combination of 2 compounds: sodium phenylbutyrate and tauroursodeoxycholic acid, also called tarso. Its mechanism of action targets a couple of different things, but it primarily targets ER [endoplasmic reticulum] stress and mitochondrial dysfunction. It hits on a couple of other things as well. There was a 6-month or 24-week study that was placebo controlled that evaluated the rate of decline of the ALS Functional Rating Scale, which is the main functional scale that we use to assess patients. People will typically lose about 1 point on this 48-point scale per month. 

In this trial, there was a slowing of the rate of decline in the treated population compared with the placebo arm. That difference was 0.24 point per month. It was statistically significant with a P value of .03. Essentially, all those numbers mean that, for a person living with ALS, time is a commodity. Essentially, there is an inherent progression of loss of function over time. This study, over the 6-month period, showed that AMX0035 was effectively able to slow down disease progression as measured by this Functional Rating Scale.

There was an open-label extension. How that was structured is this: After the placebo-controlled portion was completed, everybody was converted to the active treatment, which was AMX0035. When you looked at survival, it was published in the second publication; the initial results were in the New England Journal of Medicine, and the second publication of the survival data was in Muscle & Nerve. In that evaluation, they looked at patients who were initially started on AMX0035 and continued in the open-label extension compared with those who were on placebo initially and then converted later. 

There was a survival advantage of about 44%, which means that it is effective in line with some other approved medications like edaravone and riluzole.

A panel of experts provides insights into recent improvements in clinical trial design in amyotrophic lateral sclerosis (ALS) and discusses implications of recent clinical trial results. 

Advancements in Clinical Trial Design in ALS 

 Let’s delve into pharmacological management. We will talk about FDA-approved drugs as well as drugs in development. Ammar, riluzole, also known as Rilutek. What can you tell me about that 1?

 It is an interesting drug. It was found serendipitously, so the mode of action was thought to be related to the glutamatergic hypothesis of ALS [amyotrophic lateral sclerosis]. That is the idea that, for most neurons, when 1 neuron talks to the next neuron, it usually inhibits it. You cannot over-inhibit a neuron because it goes to 0, but some neurons excite the next neuron in the chain with glutamate, for example. It is possible to overexcite a neuron more than 100%. If that happens, then the neuron that is being hyperexcited is prone to death: to apoptosis or some similar process. That is called excitotoxicity.

Riluzole was designed because it is known to interfere with that glutamatergic transmission and modulate it to reduce it. That is why it was tried. It was trialed in the early 1990s. By 1994, it had been through a sufficient phase 3 trial that there was evidence that it provided benefit. But since then, other drugs that have a similar mode of action have not shown the same result. This suggests that the mode of action of riluzole is something different. It does not mean it definitely is, but it does make it seem more likely that it is something different, which is frustrating because if it had been the same, we would have hopefully been able to make a riluzole-plus that was better than the existing riluzole. Because it is an unknown mechanism of action, essentially, we do not know what to do to make an improved version.

 Is it always a pill, Ammar, or does it come in different forms?

 It is generally a 50-mg tablet, which is supposed to be prescribed twice a day. It is also available as a liquid, not just as tablets. If someone has a gastrostomy tube, then a liquid can be useful. In the United Kingdom, at least, the liquid can be difficult to obtain, so some people crush the tablet and add it to yogurt and put that down the tube. That is not how it is licensed to be used. Theoretically, the drug might stick to the plastic of the tube if it is not used in the correct way, but if there is no choice, then that is what people do.

When people come to me the first time, a common thing I hear is, “I heard about riluzole, but I was told it gives me only 2 extra months and it messes up my liver.” Is that accurate?

 I do not think that is accurate. Of course, there is a risk of the liver enzymes rising. It is known to do that in a portion of people. In my experience, I would say that probably about 10% of people will have that. In all the cases I have seen, stopping the drug or reducing the dose has reversed that change, and the liver enzymes have reverted to normal. In 1 case, in 27 years of prescribing it, I have seen the blood count drop. When we stopped the riluzole, it reversed. Those are known adverse effects, but they are unusual if the correct precautions and blood tests have been used. 

Addressing the 2-month survival aspect, the original clinical trial showed about a 2-month improvement in survival at 12 months. Remember, the original clinical trial was an 18-month trial, so it could not provide data beyond that. The interesting thing about it, to me, is that the technique used to come to that conclusion, the 2-month survival, was a Cox proportional-hazards regression analysis, which is a special type of survival analysis.

One of the assumptions of that type of analysis is that the change in risk is constant: It does not change during the course of the disease. In fact, it was a 38% improvement in survival that they showed, which translates to about 2 to 3 months. That 2- to 3-month improvement in survival is a percentage survival at 12 months, and you should theoretically see that improvement continued throughout the disease as an average change. Of course, we have the problem that Jeremy suggested at the beginning, which is that we do not know if everybody is a responder to the same amount or if there are some people who are bigger responders and other people who are less so, and the average is 2 months. That is probably the case. 

It is not just 2 months of survival. It is a 38% improvement across however long you would have lived. That is what the original trial says. That is different from 2 months, at 12 months, which is how people interpreted the original trial. Not all my colleagues would agree with that, but that is how I interpret that data. 

 I would say, even more strongly, that there are a host of studies that compared survival in different countries prior to the approval of riluzole and then again afterward. In the majority of those, there was some variability in the results, but the majority of those studies suggested an improvement in the life span of closer to a year. Those are not as well controlled, but they also may reflect the real world better to some extent. 

 If you were going to live 10 years, then a 38% improvement is 3 or 4 years. 

 That is a great way to look at it. Jeremy, edaravone, also known at Radicava in the United States, is another FDA-approved drug for people with ALS. What can you tell us about that?

Ammar suggested that riluzole was a serendipitous discovery. I believe that edaravone was as well. Edaravone is a drug that was developed in Japan many years ago to combat acute stroke. It is an intravenous [IV] drug and was given for 14 days as soon as the patient was admitted to the hospital with stroke. The data in Japan suggested that stroke severity was somewhat ameliorated. I do not know what the leap was to go from stroke to ALS, but there was a small academic study that looked at edaravone in ALS. 

The dose regimen was not conceived of in any particular thoughtful way. They picked the dose used for stroke, the 14 days of IV treatment, and they realized that it was probably impractical to give this to patients with ALS every day forever. They took a couple of weeks off, and they then started giving it 10 of every 28 days. It did not show a statistically significant benefit in the first trial, but it showed a trend toward some slowing of progression. The manufacturer of the drug then became more interested in it and supported a larger study, which was approximately 160 or so patients, of which 80 were given placebo and 80 were treated. It again showed some trends toward slower progression, but it was not statistically significant when the entire cohort was looked at. Subsequent post hoc analysis suggested that the earlier the patients were in their diagnosis and the more diffuse their disease was when they started treatment, the better they did. The actual amount of change in the ALS Functional Rating Scale [FRS], which was the primary outcome measure, was greater in these patients who were early onset and more rapidly disseminated early on. It was not statistically significant, but it appeared to be numerically different. If that treatment were reproduced in a bigger study, it would potentially be clinically important. 

A further study was conducted, and it was pretty small. It was about 136 patients, equally divided between treated and untreated patients, looking specifically for early onset patients who had disseminated ALS who also were progressing, at least at some criterion rates. Slow progressors were not allowed, so they took this subset that they saw the biggest change in and then did their study in those patients and found a statistically significant and clinically meaningful change in that, at the end of 6 months, the patients treated with the drug were about 33% slower in their rate of progression measured by the ALS FRS than the placebo patients. This is the study that led to FDA approval.

In the United States, there was not complete unanimity among ALS experts as to whether this was sufficient evidence to support approval. My view is that it was. It was a well-designed trial, and the effect was quite significant. Other secondary outcome measures went along in the same direction. The question was this: If the study was performed on only these patients with early onset—with rapidly progressive, disseminated ALS—is that the only group of patients that the drug works on? 

That kind of reasoning informed third-party payers’ ability or willingness to pay for a drug for ALS for a long time. My own opinion is that the investigators did a clinical trial trick that was wholly appropriate. They looked at patients that they thought, in a small, short trial, would be more likely to have a bigger effect than others, and that is whom they attended to. There was nothing, at least in my mind, about those patients that was etiologically different from the other patients. The previous study showed trend in every kind of patient with ALS toward the same beneficial effect, so my view is that the drug works. 

I encourage it for everybody. It has an attractive adverse-effect profile. It is difficult only because it requires IV access and either home- or infusion center–based therapy 10 of every 28 days.

Jinsy, you have had experience with both these drugs. Tell me about what your experience with riluzole and Radicava [edaravone] are like.

Since edaravone was approved in the United States, I proactively talk about the approved therapies at the start of the diagnosis as treatment option. We will often initiate riluzole first after a discussion of the risks and benefits, mainly because it is available in generic form, and it is available at all the pharmacies. It is easy to prescribe, and it is an oral tablet, so it is easy to take. In the United States, we have the liquid form, but it has some challenges to access because of cost. I believe there is a recently approved oral film of riluzole as well, but that is not easy to access. 

The tablet form is usually the formulation that we prescribe first. For edaravone, most patients are willing to try it and give it a shot to see how they feel. The first question I always get is, “Am I going to feel different?” This is difficult to answer because, based on the clinical trial data, we are intending it to slow down disease progression. I often have to make an analogy almost to their diabetic medications or their blood pressure medicines. They are not going to feel anything. It has an effect, but it will not be easy to tell. 

Most patients take it in our clinic at Columbia University Irving Medical Center, but that can be variable from clinic to clinic in the United States because of the payer situation and the because of physician attitude. Even people living with ALS might read the data and say, “What does that 2 to 3 months mean for me? Is that the last 2 to 3 months? If I have lost a lot of function, then I do not want to be around for that 2 to 3 months, so maybe I will not even start it.” It is difficult. In our clinic, we have 60% to 80% of patients who say, “Yes, go ahead right away.” From clinic to clinic, it can vary. It can be as low as 30% or 25% of the clinic population in the United States. That is driven a lot by physician attitude, about them thinking it is a modest medication. 

With edaravone, it is a lot newer. It has just a couple of years of experience for us. We present the data and present the risks and benefits, but the route of administration poses a challenge in our clinic. We are not able to provide the infusion at our center, so we often have to ask for prior authorization for the medication and for home nursing or an outpatient infusion center. It is a bit more complicated to access the medication, but I agree with Jeremy: For the people who have taken it, the medication itself does not pose any challenges. It is more the access to the medicine and the line management that are challenging. 

For the peripheral IV access, often we use PICC [peripherally inserted central catheter] lines, or we use a port catheter. For certain people and for several of our patients, we have had complications where either the line has a malfunction or there might be skin-integrity issues for PICC lines or infections. I have sometimes had a port-catheter-infusion site that does not heal properly, which I thought may be an ALS-specific thing because I have not had that happen in other disease populations. It is a lot of work. If anyone were to say no to it, it would be the people who might be just a little too healthy and say, “I do not want to have to do all that quite yet.” I have people who are working who do not want to maintain lines while they are doing their work, which may require physical activity. Oddly enough, living in New York, we have some people who want to go to warmer climates in the winter and swim. It is hard to manage a peripheral IV access and enjoy the beach and pool. Those are some of the challenges.

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Expert neurologists discuss clinical trial design and FDA approvals for current approaches to pharmacologic management of amyotrophic lateral sclerosis (ALS) and share personal experiences.  

Approaches to Pharmacologic Management of ALS 

Ammar, with many of my patients, after they see their primary care doctor for an annual checkup, they email me and they say, “My doctor wants to start this medicine” or “They want me to get this immunization. Should I do it? Is it going to affect my ALS [amyotrophic lateral sclerosis]?” Are there medications that patients with ALS should not take? Is it OK for them to get immunizations like the flu shot and maybe the COVID-19 vaccine?

There are some medicines that patients with ALS cannot access. For example, in Europe and in the United Kingdom, we cannot access dextromethorphan and quinidine. For pseudobulbar affect, we have to use antidepressants. In terms of medications that somebody should not take, it is largely around treatments that might interact with their existing medication, and I suppose treatments that could worsen existing symptoms, such as weakness. Those are usually obvious. The kinds of things that are going to worsen current symptoms are usually obvious.

In terms of immunization, it is important for somebody with ALS to stay up to date with their immunizations. The reason is that diaphragm weakness can occur early, so even if the person does not have symptoms, some studies have shown that up to 80% of people, right at diagnosis, have some diaphragmatic involvement even at that early stage. Of course, that makes it more difficult to clear chest infections. Most immunizations are against influenza or COVID-19, for example. They are meant to prevent respiratory infections. You are more likely to get a secondary bacterial pneumonia if you do not clear that. Immunization is important for that reason, particularly for somebody with a weak diaphragm.

Thank you. We have only briefly mentioned noninvasive ventilation [NIV]. Jeremy, tell us a bit more about noninvasive ventilation. How do we screen people for that? How do we decide when to start it? What do we start? What are the benefits?

 Noninvasive ventilation refers to a system that is interfaced with the patient using a mask or sometimes with a tube that they can sip on. In general, it most commonly refers to something called bilevel positive pressure ventilation, which means that there is air blowing out of the mask or the tube at all times, and it is triggered to the patient’s breaths. When a patient begins an inhalation, the pressure increases and allows them to fill their lungs to a greater degree than they could without it. When they stop their inhalation and begin to breathe out, the pressure declines, allowing them to breathe out more easily as well.

It mimics a ventilator for somebody who is intubated, in that the pressure increases, causing expansion of the diaphragm, and it then releases, causing a passive reduction in the volume of the lungs. It is effective for most patients with ALS who have good bulbar control. Patients who have difficulty controlling their lips or mouth or who are quite spastic in their face often have significantly more challenges in adapting to this. There are multiple studies that suggest that, when NIV is adopted at some point, it increases survival and increases quality of life, especially sleep. 

There are third-party payer guidelines that give you suggestions of when it is appropriate. In general, in the United States, it is a vital capacity less than 50% of predicted, or a negative inspiratory force less than 50% as well. These are number guidelines, but for me, I institute it when the patient history suggests that there is any kind of respiratory insufficiency that needs care. In particular, this is anybody who is having difficulty lying down to sleep, anybody who wakes up short of breath, anybody who wakes up with a headache, and anybody who feels short of breath during the day and feels like they have to stop what they are doing and just sit there.

There are standards that are more stringent than that, and they suggest that, at least in some cases, many people believe that any measurable respiratory deficit down to about 80% of normal forced vital capacity should mandate the institution of noninvasive ventilation. I have tried that in the past, but I have found that compliance is usually fairly poor. I have never been convinced that that in itself improves quality of life when it is instituted then. My thresholds may not be the same as they are for other people, but my decision is predominantly symptom-based. When somebody has a symptom that I think I can treat with that, and I have listened to them, then that is when I do it. I do not tend to do it prophylactically.

 Is that the same for you Ammar and for you Jinsy? Is it symptom-based?

 Ammar should comment because the criteria are a bit different than they are in the United States. For Jeremy and I, particularly for me, a patient has to come below half of their lung capacity, or 50% of their predicted value for forced vital capacity, to be eligible for the payer to pay for the noninvasive ventilator if we order it. I can sometimes get it if they are not that low, but if they are very symptomatic. Those symptoms can be morning time headaches, poor sleep quality, or daytime somnolence, feeling sleepy. I know that it is different in other regions. Ammar, maybe you can speak to the experience of trying to initiate it earlier and the criteria there. 

We use guidelines called the NICE [National Institute for Health and Care Excellence] guideline, which is an algorithmic process. It requires a lower threshold. If someone is symptomatic, you institute it earlier, and if they are not symptomatic, then you institute it later. Our vital capacity threshold is 70% generally, but also, if you cannot measure vital capacity, you can use oxygen saturation, or you can use sniff nasal inspiratory pressure within the guideline as well. It is a complicated algorithm, but it is what we use. It is really the same as it is for Jeremy and Jinsy: it is symptom-based, in fact.

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Key opinion leaders consider the importance of respiratory care in ALS by discussing immunization against respiratory illness as well as the use of non-invasive ventilation. 

Jinsy A. Andrews, MD, MSc

Articles

Ongoing Clinical Trials and the Future of ALS

Advancements in Clinical Trial Design in ALS

Approaches to Pharmacologic Management of ALS

Challenges of Respiratory Care in Patients with ALS