ChinaSCINet Update

[Solan]

So, probably, instead of having a clinical trial network with 25 centers non very well equipped it is better to have one center well equipped (with all kinds of electrophisiology, DTI etc.) and accept patients from all over the world.

Paolo

Interesting theory.
Have you been to China/Hong Kong and visited any of these 25centers?

Questions:
1. Where should this perfectly equipped center be located?
2. Who will finance this hosptital and trials? The local goverment is probably not gonna except paying for trails on patients not from the centers country.
3. What timeframe are you looking at for getting this organised? Be realistic! 10years, 15years?
4. Who's going to organise this project? Carecure?
5. Will you need to buy or build a new hospital for the project?
6. Isn't it better to have the trail in 25 hospitals, that probably are doing their best with the resources they have, today, then having the perfect trail, in a perfect location, for the whole world, sometime in the future?

[KIM]

I rather have scientist of all the world working on different approaches than one mega centre with one therapy.

[crabbyshark]

So, probably, instead of having a clinical trial network with 25 centers non very well equipped it is better to have one center well equipped (with all kinds of electrophisiology, DTI etc.) and accept patients from all over the world.

This is false. The logistics of doing that would slow things down considerably without necessarily demonstrating better results. It would also be more expensive.

The ceramics teacher announced on opening day that he was dividing the class into two groups. All those on the left side of the studio, he said, would be graded solely on the quantity of work they produced, all those on the right solely on its quality. His procedure was simple: on the final day of class he would bring in his bathroom scales and weigh the work of the “quantity” group: fifty pounds of pots rated an “A,” forty pounds a “B,” and so on. Those being graded on “quality,” hoever, needed to produce only one pot – albeit a perfect one – to get an “A.”

Well, it came grading time and a curious fact emerged: the works of the highest quality were all produced by the group being graded for quantity. It seems that while the “quantity” group was busily churning out piles of work – and learning from their mistakes – the “quality” group had sat theorizing about perfection, and in the end had little more to show for their efforts than grandiose theories and a pile of clay.

DTI is important but less so than results. A guy doesn't need an MRI of his brain to verify that after drinking too much beer, he's become drunk.

[Moe]

To me 25 networked trial centers not fully equipped but share the same basic procedure is more efficient than one only center that is. Ordinary clinics or family doctors aren’t even all equipped with an x-ray machine, so when one is needed, the patient is sent to a place like a hospital to have one done, then the doctor receives it to continue his/her evaluation. So what would be the difference for an MRI or any other equipment? Just send the patient somewhere else to get an MRI or to exercise any other therapy if not so equipped…

Crabbyshark has a point that I wouldn’t really care too much for DTI or any other imaging equipment, unless its needed to analyze the injured site before treatment. Besides that it’s not like if we can’t feel the results of gaining or not motor/sensatory functions afterwards… don’t need a machine to tell me that…

[paolocipolla]

I hope that gives a better idea of what I wanted to say:

"Since money is the central issue here, Schwab and Buchli suggest two things: use what we have more wisely and seek new partners for funding:
Instead of investing billions in one drug, let’s spread funding among smaller, proof-of-concept trials for compounds with good preclinical evidence. By focusing on well-selected populations (with tens of patients, not hundreds) and concentrating on a few centers, such trials would cost a few million euros rather than the €50 million (US$67 million) or more needed for one large trial."

http://www.spinalcordinjury-paralysi...-neurosciences

Paolo

[crabbyshark]

I hope that gives a better idea of what I wanted to say:

"Since money is the central issue here, Schwab and Buchli suggest two things: use what we have more wisely and seek new partners for funding:
Instead of investing billions in one drug, let’s spread funding among smaller, proof-of-concept trials for compounds with good preclinical evidence. By focusing on well-selected populations (with tens of patients, not hundreds) and concentrating on a few centers, such trials would cost a few million euros rather than the €50 million (US$67 million) or more needed for one large trial."

http://www.spinalcordinjury-paralysi...-neurosciences

Paolo

Homie, are you trollin right now? Do you not see that this is exactly what is happening? 1-2 centers, tens of patients.

Preclinical evidence in animals suggested that umbilical blood cord monocular cells were helpful for regenerating animal spinal cords. SIXTEEN people (not hundreds) in Hong Kong received UCBMC. The results might indicate that some subjects reported regaining a little sensation and that DTI suggests the white matter of the spinal cord is regenerating.

In Kunming, FOUR people received 6.4 million stem cells and FOUR people received 6.4 million+MP. Some of these people might now be walking. That's EIGHT people (not hundreds). The results of FOUR people who received UCBMC + MP and did a 6 week course of lithium (which has shown in preclinical animal trials to act as a sort of stem cells fertilizer) are getting collected now.

This is TWENTY EIGHT people (tens, not hundreds) undergoing "smaller, proof-of-concept trials for compounds with good preclinical evidence." It seems there might be proof that these concepts are effective. If this proof exists, then it is probably advantageous to move forward and try the therapies on a larger group. The plan seems to be to try doing this with 120 subjects (still not hundreds) for $12 million dollars (not $63 million) in 1-2 centers in the United States.

SCINet is like one giant, awesome SCI therapy hospital.

Let's say I get hungry and the only place to eat is McDonald's. In this scenario only one McDonald's exists, and it located in Los Angeles. This McDonald's is the size of four Wal-Marts. It has every single McDonald's amenity you could possibly imagine. Because I am hungry and there is no other place to eat, I fly to McDonald's, get my food, and then fly back to Ohio.

McDonald's decides one day to expand their franchises to make it easier for customers to reach. The new McDonald's all have the same logo and offer the same food. The staff at one McDonald's functions the same as the staff at another McDonald's. However, some of the new McDonald's have playgrounds and some others serve alcohol. These aren't primary reasons customers go to McDonald's, but they can be good things for McDonald's to offer to entice some people to eat at that particular McDonald's as opposed to another one.

SCINet is McDonald's. Not every hospital participating in SCINet is going to have diffusion tensor imaging machines. That's ok though because diffusion tensor imaging is tricky and is hardly the only means to evaluate efficacy of an experimental therapy. Every hospital participating in the network will meet requirements allowing them to participate in the network. The staff at one hospital will be trained the same as a staff at another hospital. The hospitals participating in the network will be able to easily share information with one another. 1 or 2 of the most experienced hospitals participating in the network could be designated to be the first to try a brand new therapy on tens of people.

Technology and communication makes it unnecessary for all researchers to be under the same physical roof. These clinical trial hospitals could go on to become the first hospitals to offer actual therapies proven to work. These are all very good things.

[beuty]

I wanted to address one of Lynnifer's comments. She pointed out that she doesn't see many people lining up, presumably with therapies for the trials to come whether umbilical cord blood and lithium turn out to be effective. Many companies and investigators have approached ChinaSCINet to test therapies. Let me mention just a few that we are working with.

1. Cethrin. We are working with Lisa McKerracher to bring Cethrin to phase 3 trial. For example, we are hoping to do a U.S. phase I/II trial comparing UCBMC+lithium and UCBMC+lithium & Cethrin. This would be precursor to a phase III trial comparing UCBMC+lithium, Cethrin, and UCBMC+lithium & Cethrin. Since we now have phase I/II safety data for UCBMC+lithium and Cethrin in chronic SCI and Phase I/II safety data for Cethrin in subacute spinal cord injury, we believe that we can get regulatory approval of use of the combination of the three treatments for chronic SCI relatively quickly, as soon as GMP facilities can be identified for manufacturing the Cethrin.

2. Soluble Decoy Nogo Receptor. We are working closely with Axerion to test and move their soluble decoy nogo receptor to trial. Strittmatter has published exciting chronic spinal cord injury animal results, showing that this treatment improves recovery of function in rodents. The treatment appears to be safe (because the soluble nogo receptor protein binds to molecules that bind to the Nogo receptor). This could be tested in combination with the cells transplants mentioned below.

3. HLA-matched UCBMC-derived Muse cells and autologous Schwann cells. We are working with Mari Dezawa in Japan to isolate and expand Muse cells from UCBMC. UCBMC can be HLA-matched to recipients with spinal cord injury. These are pluripotent stem cells that can generate neural stem cells to replace motoneurons and interneurons in the spinal cord. We hope to combine Muse cell transplanted into the lumbosacral spinal cord with Schwann cell transplants into the ventral roots, to entice motor axons to grow into the ventral roots to re-innervate muscle. We have developed a lumbosacral spinal cord injury model in rats to test these therapies. We are hoping of course that Miami project will have good results with their Schwann cell trials so that we don't have to do phase I trials of Schwann cells to show safety.

4. Neural stem cell lines. We have been following the trials that Neuralstem and Stem Cell Inc. have been doing. If those trials prove to be positive in chronic SCI, we will be ready and willing to take these cells to clinical trial in ChinaSCINet. These could be with the cells on their own or in combination with some of the above therapies. While I remain skeptical that these cells will survive long enough to replace neurons in the spinal cord, I think that these cells may well be an excellent source of growth factors and "come-hither" signals that could stimulate regeneration in the spinal cord as well as HLA-matched umbilical cord blood mononuclear cells.

5. Umbilical cord lining (UCL) cells. We are working with a group in Singapore to test UCL cells that are mesenchymal stem cell like and express HLA-G, an anti-immune protein that prevents rejection. These cells have many interesting properties, including ability to repair cornea, liver, and skin. Because they express HLA-G, they are immune-privileged.

6. Placental cells. We are working with Celgene to develop and test placental cells and other products in spinal cord injury. The placenta contains many immune-privileged stem cells and probably is the source of the stem cells in umbilical cord blood and also umbilical cord lining. These cells transplants can be tested in combination with all the other therapies, including PTEN, CSPG receptor blocker, lithium, etc.

So, there are many therapies waiting in the wings. There are some that I haven't mentioned because we are still waiting for decisions by the companies. For example, the Nogo antibody is still "floating" and we have not yet seen the published data concerning the trial. We are of course watching the work by Kai Liu and Jerry Silver carefully. Although Liu has shown that knocking out PTEN allows many corticospinal axons to grow across the injury site, the growth of the axons is very slow (slower than 1 mm per day) and one possibility is that CSPG or other axonal growth inhibitors are slowing down the axonal growth across the injury site. So, one approach will be to combine both therapies. Much still needs to be done before a genetic therapy knocking out PTEN can be taken to trial. We are exploring other pharmaceutical means of down-regulating PTEN.

Wise.

have you considered autologous stem cells transplantation (mesenchymal, hematopoietic etc ...)

[paolocipolla]

Homie, are you trollin right now? Do you not see that this is exactly what is happening? 1-2 centers, tens of patients.

Preclinical evidence in animals suggested that umbilical blood cord monocular cells were helpful for regenerating animal spinal cords. SIXTEEN people (not hundreds) in Hong Kong received UCBMC. The results might indicate that some subjects reported regaining a little sensation and that DTI suggests the white matter of the spinal cord is regenerating.

In Kunming, FOUR people received 6.4 million stem cells and FOUR people received 6.4 million+MP. Some of these people might now be walking. That's EIGHT people (not hundreds). The results of FOUR people who received UCBMC + MP and did a 6 week course of lithium (which has shown in preclinical animal trials to act as a sort of stem cells fertilizer) are getting collected now.

This is TWENTY EIGHT people (tens, not hundreds) undergoing "smaller, proof-of-concept trials for compounds with good preclinical evidence." It seems there might be proof that these concepts are effective. If this proof exists, then it is probably advantageous to move forward and try the therapies on a larger group. The plan seems to be to try doing this with 120 subjects (still not hundreds) for $12 million dollars (not $63 million) in 1-2 centers in the United States.

SCINet is like one giant, awesome SCI therapy hospital.

Let's say I get hungry and the only place to eat is McDonald's. In this scenario only one McDonald's exists, and it located in Los Angeles. This McDonald's is the size of four Wal-Marts. It has every single McDonald's amenity you could possibly imagine. Because I am hungry and there is no other place to eat, I fly to McDonald's, get my food, and then fly back to Ohio.

McDonald's decides one day to expand their franchises to make it easier for customers to reach. The new McDonald's all have the same logo and offer the same food. The staff at one McDonald's functions the same as the staff at another McDonald's. However, some of the new McDonald's have playgrounds and some others serve alcohol. These aren't primary reasons customers go to McDonald's, but they can be good things for McDonald's to offer to entice some people to eat at that particular McDonald's as opposed to another one.

SCINet is McDonald's. Not every hospital participating in SCINet is going to have diffusion tensor imaging machines. That's ok though because diffusion tensor imaging is tricky and is hardly the only means to evaluate efficacy of an experimental therapy. Every hospital participating in the network will meet requirements allowing them to participate in the network. The staff at one hospital will be trained the same as a staff at another hospital. The hospitals participating in the network will be able to easily share information with one another. 1 or 2 of the most experienced hospitals participating in the network could be designated to be the first to try a brand new therapy on tens of people.

Technology and communication makes it unnecessary for all researchers to be under the same physical roof. These clinical trial hospitals could go on to become the first hospitals to offer actual therapies proven to work. These are all very good things.

Crabbyshark,

I get your points, but I am afraid you don't get mine very well... I don't know how to explain myself better than I did already on this issue, so I just leave it like that and people are free to come to their own conclusions, by reading all the posts.

We may just agree to desagree.

About your example of McDonalds, in my opinion, it is not a very good example as when Mc. comes out with a new product from their research dep. they try it in only a few locations first. Also there is a little set up cost to offer a new tipe of food, it's not like trainig a medical team to do a clinical trial.
Your McDonalds example IMO may fit better if you consider a treatment that has been proven effective after phase III and needs to be made available to the general public.

Paolo

[crabbyshark]

"Since money is the central issue here, Schwab and Buchli suggest two things: use what we have more wisely and seek new partners for funding:
Instead of investing billions in one drug, let’s spread funding among smaller, proof-of-concept trials for compounds with good preclinical evidence. By focusing on well-selected populations (with tens of patients, not hundreds) and concentrating on a few centers, such trials would cost a few million euros rather than the €50 million (US$67 million) or more needed for one large trial."

http://www.spinalcordinjury-paralysi...-neurosciences

About your example of McDonalds, in my opinion, it is not a very good example as when Mc. comes out with a new product from their research dep. they try it in only a few locations first. Also there is a little set up cost to offer a new tipe of food, it's not like trainig a medical team to do a clinical trial.

In the first post, I feel like you are implying it would be good to try new therapies in only a few locations first. You even put it in bold. In the second post, I feel like you are implying it would be bad to try new therapies in only a few locations first.

Yes, little set up cost ($12 million vs $67 million). The medical team doing the initial trials (on tens of patients, not hundreds) would likely be the same medical team that developed the therapies in the first place (exactly what is happening in Kunming), and would not need training.

[crabbyshark]

Paolo,

I think you might be confused about the meaning of what was said in the article you cited. They are not implying we have one or two super duper major clinical trial centers. They are suggesting that when we do a clinical trial for a new therapy, we do one specific trial at one specific hospital, on a small group of patients that meet very specific criteria and would preferably live in a specific area where the same investigators can easily follow-up. China is perfect for this because there are so many people. It doesn't matter where the hospital is or how big the hospital is so long as it is capable of carrying out the procedure.

They are contrasting this with the current method of a researcher showing promising preclinical data of a drug or therapy to a pharmaceutical company and the pharmaceutical company investing in it and running the clinical trials. The pharm company runs the trial using hundreds of patients and doctors and hospitals from all over the country, or maybe even the world. This is expensive and inefficient. If the drug fails it is a big financial loss. When they say "seek new partners for funding" they could have added "besides pharmaceutical companies."

If the trial results in Kunming show the therapies are safe/working, the researchers would then approach investors (you, me, justadollarplease.org, colleges, NFL, Red Bull) to fund the Phase III trial. If Phase III is good to go, a company could then confidently invest in a therapy that works and push it to the masses. This is much more efficient for every single entity involved in the process.

[Barrington314mx]

Im sorry, but I am majorly confused. The talk about this trial is in so many directions that I dont know whats what. Not to mention Wise Young saying they arent showing improved motor or sensory scores. But in one video says that a patient could feel that his leg was fractured and in another video says that a patient complained of increased neuropathic pain but the improved return was worth it.
Sorry but I think this is too unclear and confuse able. And that might not be good for raising money.

[crabbyshark]

Im sorry, but I am majorly confused. The talk about this trial is in so many directions that I dont know whats what. Not to mention Wise Young saying they arent showing improved motor or sensory scores. But in one video says that a patient could feel that his leg was fractured and in another video says that a patient complained of increased neuropathic pain but the improved return was worth it.
Sorry but I think this is too unclear and confuse able. And that might not be good for raising money.

In the very first clinical trial done around 2 years ago in Hong Kong, 16 people were given a low dose of umbilical cord stem cells. Some of these people have shown sensory improvement of one or two segmental levels (this returned over a long period of time). These subjects received no physical therapy, MP, or lithium.

In the more recent trials (6-12 months ago) the subjects received higher levels of stem cells + MP and physical therapy. There may be indications some subjects are walking without yet getting sensation or voluntary movement back.

We might conclude from this info that return varies. A possible outcome of a subject getting UCBMC+physical therapy might be that they start walking in six months and then in two years begin to feel their feet. People are improving but it takes time. The procedure isn't an instant miracle cure-all.

I understand how you feel about being confused sometimes. I think it is probably hard for Wise, knowing everything he knows about the actual results of the trials, to read posts by people on carecure dealing with deep SCI-related depression (some to the point of being suicidal) and not feel some moral obligation to let them know that there is hope. So what he gives are purposely-not-always-completely-clear answers that amount to "we are getting there, don't give up yet!" Some people get mad precisely because the answers not crystal clear. I would bet though most people here are at least a tiny bit excited by the message, even if they don't completely understand all the words.

Hopefully, collection of the 6 month follow-up data of the June subjects is going super smoothly... then there will be good, solid info to share by the end of the year.

[Barrington314mx]

We might conclude from this info that return varies. A possible outcome of a subject getting UCBMC+physical therapy might be that they start walking in six months and then in two years begin to feel their feet. People are improving but it takes time. The procedure isn't an instant miracle cure-all.

Im fine with that. Where do i sign up.
Seriously, thats the best thing we would have to date. So i would hope that even if thats the case, that itll be enough to move it forward.

But thanks for your explanation. Im definitely not mad at anyone or anything. I took everything that Wise has said in his videos as good news. But then I come on here and read not so positive posts and start to wonder if i miss interpreted what he had said in the videos.

[Wise Young]

Crabbyshark,

Thank you for doing such a good job explaining the ChinaSCINet results. Let me correct or more fully characterize a few findings:

1. The two Hong Kong centers transplanted cells into 8 subjects, only 4 µliters x 4 and 8 µliter x 4 injections into the spinal cord and did not test the 16 µliter x 4, of 16 µliter x4 and MP, or 16 µliter x 4 with MP and 6 weeks of lithium.
2. The Kunming center transplanted cells into 20 subjects, including the 4, 8, and 16 µliters x 4 injections, the 16 µliters x 4 with MP, and the 16 µliter x 4 with MP and a 6-week course of lithium.
3. Of the 8 subjects studied in Hong Kong, only 5 had good enough MRI to allow the DTI to show the white matter. Of the 5, two subjects showed evidence of white matter regrowth across the injury site. Unfortunately, in these subjects, we did not find a correlation with neurological function. We are continuing to follow these subjects.
4. Of the 20 subjects studied in Hong Kong, we have not yet analyzed the 6 months data. Based 6-week and 3-month data, we are seeing improvements in walking scores without improvements in ASIA motor or sensory scores.

I hasten to point out that this was a talk that was addressed to scientific colleagues at a workshop on the subject of obstacles to clinical trials. I was discussing two findings in our trials that I felt needed discussion by the scientists in the audience. If this talk were for the spinal cord injury community, I would have spent a lot more time explaining why regeneration is likely to take years and that axons have to grow upward all the way from the injury site to the brainstem to restore sensation and downward all the way from the injury site to the lumbosacral spinal cord to restore voluntary leg movements. Also, axons don't have to restore voluntary movements in the legs in order to restore walking motions. I did not cover these issues because the audience that I was speaking to, including the top scientists in the field, know these concepts well.

Let me describe our interpretation of the two major findings that I presented to the scientists.

First, we found that evidence of white matter regrowth in 2 of 5 subjects after UCMBC transplants, not just across the gap but apparently long distances both up and down the spinal cord. All ASIA A subjects showed a white matter gap before treatment. None had shown white matter growth across the gap before cell transplantation. The growth does not seem to correspond with motor and sensory scores in the subjects. We believe that this may be because the growing fibers have not yet reached their targets, i.e. have not connected with neurons in the brainstem that would be necessary for sensory improvement or in the lumbosacral spinal cord for voluntary activation of the leg muscles.

Second, in Kunming, while some subjects are taking steps, they are not showing improvements in their motor or sensory scores. We believe that this is occurring because some growing fibers have made connections with the central pattern generator and this is what is activating the walking activity without improving motor or sensory scores. Incidentally, this is not surprising. Most people who recover walking and even ability to run long distances in marathons, i.e. so-called walking quads or paras, don't have normal motor or sensory scores in the legs. I emphasized that these results are very early and that perhaps motor and sensory scores will show more change on later examinations.

Because of the widespread misunderstanding of what was presented, I am reconsidering presenting any more data from these trials until the trials are complete. People are jumping to unwarranted conclusions.

Wise.

P.S. I moved some of the posts to the Members Only Forum because they are unrelated to ChinaSCInet, which is what this topic is about.

[Wise Young]

have you considered autologous stem cells transplantation (mesenchymal, hematopoietic etc ...)

Yes, we have considered and are considering autologous cells. These include of course autologous OEG cells from the nasal mucosa and autologous bone marrow cells. Wise.