Do you see FDA taking a different stance on approval process in light of how fast COVID-19 clinical trials are proceeding?
I do think that the FDA has shown, by issuing the guidance, a remarkable openness to flexibility regarding how we move forward in this really unprecedented time so that research can continue. Whether that will lead to changes in approval processes, we have not yet heard. I do think the FDA did a major shift forward because of all the advocacy in general on ALS and hopefully that will continue.

Are the folks at the FDA that are dealing with the COVID-19 infection crisis the same ones that are dealing with the ALS drug review?
I think that there are probably different people reviewing the COVID-19 and the ALS drugs because it's not neurological. It is possible that they might need extra people and could call on some of the neurology people to help just like some hospitals that are calling on neurology teams to help their medicine colleagues.

Do samples collected in clinical trials require special handling?
For a long time we have had standard precautions that we use when handling blood, spinal fluid and urine from patients. Many of those precautions came into existence around the time of the HIV crisis that taught us that we actually ought to be very careful in a very specific way and they continue now. If we follow what we call universal precautions we can prevent any infection of healthcare workers who are dealing with samples and I would say that we are likely to learn something about universal precautions in some way out of this current outbreak in a very different way. But because of universal precautions, we feel safe handling samples.

Is it possible that in this COVID-19 crisis that staff will be pulled from clinical trials into the front lines of dealing with the infections and treating patients with COVID-19?
This is a difficult period and definitely uncertain times, but for the most part, I think in terms of New York City many of us that are working in clinical trials for ALS have been reserved for continuing our work in ALS. I think that's a really positive indication about keeping the trials moving forward. Of course, as the situation evolves, it will really depend on local situations that arise and state regulations. 

It will definitely depend by city and location, but I think it is a real risk the nurses in particular from the ALS centers and also the physicians could be called to help our medicine colleagues and help our patients so that that might lead to some more time to answerphone calls. But the commitment to push ALS forward and care for our patients is always front and center.

Can you share the Healey Platform trial timeline and approved locations? And will there be any difficulty in moving the platform trials forward?
Please join the April 8th webinar where we will provide as many details as possible. So the good news on the platform trial is that we have FDA approval for the first three regimens and we actually also have Central IRB approval for the first three regimens and we did training remotely for all our 54 centers, but there's still a lot of work that we have to do. We are putting in an amendment to the protocol to make it a little easier and we are now working with all the sites to get them ready. We don't have a timeline yet of when it's going to be ready to enroll.  We're also paying very close attention to the issues we discussed about when it is safe for people to be able to come to the center to enroll. So we hope to have a little more information on the April 8 webinar, but we want everyone to know that team is working really hard to keep any pause as short as possible and to do it as safe as possible.

Will covid-19 infections affect or interact with the treatments that will be chosen for the platform trial?
That's an excellent question and the answer is no. We've talked to all three of the sponsor drug companies involved with the first three drugs and there's no risk for people related to COVID-19.

Is there any news on the Radicava oral trial?
This is a is a great example of a trial that is primarily in start-up phase at many centers. That start-up work is continuing so contracts, trainings, getting all the pieces put in place are ongoing. Like other trials, it may impact the enrollment timeline, but we just have to see and that may be different location by location.

I’m going to be starting Radicava soon and was going to take the medicine via a port rather than a PICC line.  What is recommended now?
That question is very much in the clinical realm and the first thing I would say is that anybody with a question like this should talk with their treating physician to help make these decisions but let me back up and just talk about a few principles. There are different ways to get to that IV space at home. A PICC line (peripherally inserted central catheter) as a line that goes in the arm and can be accessed like an IV but can stay in longer. We think about risks like infection but we're really thinking about primarily bacterial infection where that catheter enters or along the line of that catheter when we when we talk about that. A port has to be placed through a procedure which is done at a hospital and so I think when we're talking about the differences now, we're really talking about the practicalities of do you have to go somewhere to have this placed? How much exposure does that potentially put you at risk for? The other thing to think about is just making sure that you're using all the safety precautions if people are coming into your home to help you with something like Radicava.

What is the current status of the SOD1 and C9 trials sponsored by Biogen?
The most important point is that it's going to be institution to institution dependent. It depends on where the patient is getting dosed and what the rules are at that institution and each institution is doing this differently. Every institution is trying to minimize risks and yet continuing some of these important ongoing trials. At our institution (Washington University in St. Louis) patients with the SOD1 ASO are continuing to get dosed though we're trying to make as many arrangements as possible to make it easier for all those participants.

We are continuing as well (Emory ALS Center) for the patients who are already enrolled and are already receiving either the SOD1 or the C9 antisense oligonucleotide and what we have done is applied to our research administration saying that this is essential to keep these patients on the drug and they've approved and that's not going to happen at every institution and a lot of that is going to depend on resources as well. We currently have space to do this but as this COVID-19 pandemic gets worse potentially we may lose that space. So, there's some practicality here that goes along with the safety. And so again, if you're in that trial, I'm sure that you've already discussed this with the investigator at your institution, but also things might change as we move forward and they may get more difficult or they actually may get easier as things get better. And the other thing is that we are not enrolling any new patients into these trials at this point and we are going to wait for that until the pandemic simmers down a little bit.

Do you know if the T-reg study from MGH will be on hold or will it be able to continue at some point?
The T-Reg study is another study that we're not only delivering by IV, but there's some pre-release testing of the cells that has to be done. So that has to be done here and likethe Brainstorm study and the ASO study that you've heard about a little bit for the T-Reg study we've made adjustments so that we're minimizing the times that people have to be here at the hospital by doing some of our assessments remotely, doing good screenings for people before they come in, and continuing to allow people to have their monthly treatments for the trial.

Can you share any insights, feedback or observations on the current NurOwn stem cell trial for ALS?
Since NurOwn has to be delivered by intrathecal administration in the spinal fluid, all the sites are trying to do their best to keep people coming in on schedule so that study can complete and to do that safely and do every other part of that study as remotely as possible, but it is continuing to see the people who are enrolled in that study.

There have been a few adjustments in the trial overall that that are meant to keep things moving forward. Vital capacity is not being performed until that's thought to be safe to do that. There are provisions to do non-treatment visits in the study. We see people sometimes for visits where we're evaluating them evaluating safety, but not treating them with actual product. Those can be done remotely. This is a trial where we had been keeping people overnight after we treated them with the stem cells and we are amending the protocol now at all of the sites to allow somebody who is stable to not have to be in the hospital overnight. That works to reduce the burden of the trial on the hospital. It also reduces the potential for exposure of the participants in the trial. So kind of a win-win there.

How is COVID-19 affecting any projected or planned trials?
There are a number of trials that were due to start this spring, summer and fall and there's a number of Pharma sponsored trials that are just about ready to go. Investigator meetings that were scheduled to be held in the US, Europe and Asia have all been continuing but they've been changed to remote meeting so that just like we're doing now we're having a large group meeting to talk about things like how to get sites up and running to run these trials. At the moment, I'm not aware of any company that is planning to start a trial in the current environment. Everybody is adopting a wait-and-see stance. I think that while there is a lot of variability and where individual fights are in terms of seeing patients that are already enrolled in trials, my impression is that most clinical sites have stopped enrolling new patients. So, I think the companies have recognized this and are basically chomping at the bit ready to go and doing all the work necessary to be able to start right away. So just as was talked about for the Healey trials and for other trials, they are doing contracts, site training, each site initiation visits where somebody comes and does the final training before you start. To the extent that institutional review boards are willing to make rulings on non covid-19 related trials that's going forward. So everything is ramping up just waiting for the ability to move.

Are there any interventional studies underway that are in danger of being cancelled if the participants can't follow the treatment protocol due to COVID-19 restrictions?
Being in New York City at Columbia University, we're at the epicenter of the COVID-19 outbreak and what I can say is it is variable as Merit mentioned earlier from region and institution depending on how rampant the outbreak is. In New York City we do have some difficulties in continuing the studies. On Monday it seemed that things were able to continue and then as the cases of COVID-19 infections increased, but the situation evolves and is very dynamic. What I can tell you is that for ongoing clinical trials, the IRB at our institution and also the hospital leadership for operations has a very good understanding especially because I was able to provide the FDA guidance document which highlights risk/benefit from an ALS patient perspective. They are trying to find ways to help continue these protocols and maybe creating a slight delay in dosing or visit schedule but not stopping them. I think everyone, even people who are not familiar with the ALS space, realizes how critical this is to patients and caregivers. So even in the in our affected area in New York City we’re able to continue in some way shape or form to keep things moving forward.

Can you clarify what Curcumin is, how that trial would be run, and what does it mean to be virtual?
I run this program called ALSUntangled and in that program, we take ideas from patients and families around the world about alternative and off-label treatments that might work for ALS and I've got a whole team of people now, clinicians and scientists from across 11 different countries more than a hundred of us, that work together to write these reviews in a very structured way. Unfortunately most of the things that we've written about so far don't seem to be very promising at least promising enough to take into a pilot trial but an exception to that was curcumin which is a molecule that's found in a lot of spices including turmeric and curry powder. There's actually lots of data from test tubes and animal models that suggest that curcumin might be able to do things that could be useful to people with ALS. It's an antioxidant. It's an anti-inflammatory. It inhibits protein aggregation. It might change the fecal microbiome. There's actually a couple of clinical trials of curcumin done outside the United States that suggested some benefits and amongst the cases of ALS reversals that I've collected six of the 47 were taking some form of curcumin when they started to get stronger. So, for all those reasons, I think it's promising enough to take into a clinical trial. The specific brand of curcumin that I'm going to study is Theracurmin and the reason is there's actually some really nice pharmacokinetic data on that suggesting that it gets into the blood and probably the brain and it also is the one form of curcumin that I'm positive changes the microbiome, at least in animal models. I've got the company under contract to give me the medicine to use in my trial. I've got PatientsLikeMe under contract to be the database for the trial and this trial will be entirely virtual meaning that patients will never have to travel to any site to participate in this trial. We will consent them from their homes. If they pass consent, we will train them on how to do some of the patient reported outcomes from their homes. We will train them on how to use PatientsLikeMe. We will check in on them. We will send the products to their homes, we will even send kits to collect microbiome samples and to send those back through the mail to me here at Duke where we can analyze them. So, I think it's one of the first entirely virtual clinical trials. But again, it's important to understand that the reason we can do this is that curcumin is a product that the FDA thinks is really safe. That's why it's allowed to be sold in grocery stores and on amazon.com and we're looking for a huge effect here. I mean, it's a long shot. We might miss a small effect with a design like this, but that's the purpose of the study.

If a trial was using SVC as a key measure, will they allow an alternative measure? Is there insurance concerns that could affect a trial?
The use of FVC in a clinical trial as an outcome measure is obviously quite important as Dr. Shefner said earlier, but it would really be up to the sponsor to change the protocol of the clinical trial to have a different measure of breathing. There are some other potential non-quantitative or less quantitative measures of breathing like counting or speaking for a certain period of time but I don't know of any trials that have used that. The only thing I'm aware of is that for most clinical trials that we're involved in we've stopped doing that. The issue of insurance again, you should speak to your clinician about that. I've spoken to our pulmonologists about other ways to get people the BiPAP or the trilogy machine that they need in terms of clinical care and there may be some ways other than doing a vital capacity in order to get that but you need to speak to your clinician about that.

Do home measures need FDA approval to be used in clinical trials?
Any new measure needs some sort of FDA approval in order to allow them to bill for this in normal clinical use. In clinical trials you don't need FDA approval. If there was any kind of risk associated with it, then yes.  It is true that the FDA may not accept those the measures that I was talking about, in particular things like electrical impedance myography or even home SVC, as a primary outcome measure as the reason to approve or not approve a drug unless it's gone through some kind of FDA certification, but we don't have to wait for that to use the measures to gain information about the methods themselves and also to potentially give us important information about the disease.

Does a study need unanimity, consistency across all sites, to continue ongoing clinical trials like the Biogen C9 trial? For a multi-site trial to proceed, do you need unanimity on the procedures and protocols?
Overall with trials you don't need unanimity to continue.   Some centers may be able to move forward and others cannot.   Each company has their own approach and a company like Biogen, for example, has a different approach to some trials versus others and they may be themselves slowing down some programs if they feel it's appropriate to do so.  In terms of specifically the question for the ASO trials, C9 and SOD1 both of those trials can continue at individual sites even if a particular site decides that they need to put on pause for one reason or another.