ChinaSCINet Update

[Skipow]

[QUOTE=Wise Young;1626637]

In the U.S., we are planning a phase II trial to compare subjects that are randomized to 6:6:6 (i.e. 6 hours a day, 6 days a week, for 6 months) to 3:3:3 (i.e. 3 hours a day, 3 days a week, for 3 months) training programs. This is supposed to establish feasibility. Each participating center will have a rehabilitation only group, consisting of 3:3:3 training and encouragement for the subjects to "walk to tolerance" in the remaining time. In the phase III trials, we plan to compare rehab only, UCBMC transplant only, lithium only, and UCBMC+lithium. I am worried that if we don't have a intensive locomotor training program in the U.S., we will not see any locomotor recovery.

Wise.

Wise,
Where in the US are you planning on doing these studies? Will it include all ASIA classifications? Has there been any "non-formal" research on the 3:3:3 vs. 6:6:6 research? I've heard that some researchers feel that locomotive training is more effective by assisted walking, if possible, rather than using a body weighted treadmill (Therastride, Locomat), due to limited side gait mobility in the hips and other things, whats your take on this? What type of locomotive training or exercise regiment is part of this routine? Does this involve other excersizes such as FES and strength workouts? What do you feel would be the difference and requirements from "intensive" locomotive training to "normal" locomotive training?

Thank you!

[c473s]

There is no "routine" protocol for locomotor training. NRN utilizes the manual treadmill, the Lokomat utilizes robotic motion and once you advance the Zero G can be utilized to simulate over ground more realisticly while preventing falls.
NRN for 1.5 hours 5 days a week is hugely expensive from a labor standpoint. The data is not yet complete for Zero G or overground. One can utilize a swimming pool for chest deep walking once there is volitional control and get very good results.

[Wise Young]

[QUOTE=cripwalk;1626663]

Wise, I can only assume that double blind/blind trials are being utilized over simple mathematical significance because of the limited number of patients available to test. Is this correct? Presumably a higher 'n' would give clearer and more convincing results but pragmatics (time/money/availability of subjects) prevent this from happening?

cripwalk,

I am not sure that I understand your assumption or question. Double blind trials are not being utilized because of any change in mathematical significance. The standard statistical significance tests will be utilized. The reason that treatments are double-blinded is to avoid placebo effects and evaluator bias. Double blind refers a trial in which both the subjects and evaluators do not knowing what therapies they have received.

Obviously, one cannot double-blind locomotor training because both the subjects and the evaluators would know that the training is or has occurred. Cell transplants can be double blinded by comparison of the treated group with a group that received sham surgery but no transplants were placed (as you can probably imagine, this is difficult to do and considered unethical by some people). Drugs can be relatively easily double-blinded by having the subjects take a pill that has the active ingredient or a "placebo" pill that has only inert ingredients.

A generally accepted probability is 0.05 for significance, i.e. 1 in 20 chance of error. The preferred statistical test is ANOVA (analysis of variance) for comparison of two or more treatment groups. The number of subjects per treatment group (n) can be calculated based on an assumption of 0.05 p-value (alpha) and an assumed effect size (see http://www.math.yorku.ca/SCS/Online/power/)

Wise.

[Wise Young]

Which evidece?

Scaffolds could be usefull in many ways to repair the spinal cord. As far as I know at this stage of research I see it difficult to say for sure if they will be needed or if they will not be needed.
If you know that for sure, it would be good if you could provide real convincing evidence to support what you say.

Paolo

Paolo,

I am not sure where you get your information concerning scaffolding but I don't find much credible data supporting their use for repairing spinal cord injury in clinical trials for the following reasons:

1. There is no easy way of putting scaffolding inside a contused spinal cord without damaging the cord further. Most of the studies that I know have used transected spinal cords and placed the scaffold between two cut ends of the spinal cord. As you know, transected spinal cords are exceedingly rare.
2. Regeneration of axons through a scaffold faces two difficult obstacles. The first is to get the axons to grow into the scaffold. As Xu Xia-ming showed, this can be done by filling the scaffold with Schwann cells. The next obstacle is to get the axons to grow out of the scaffold into the surrounding cord. A few treatments (such as combination neurotrophins) seem to do this but the results have been modest, at best.
3. Some investigators have proposed that the spinal cord can be transected and the scaffold be put between the cut ends. I am not convinced that this is better than injecting cells into the spinal cord surrounding the injury site. The cells migrate into the injury site and form a continuous living bridge across the injury site.

So, perhaps you can tell us where you have gotten the impression that scaffolding is so promising. What studies are you referring to?

Wise.

[Wise Young]

[QUOTE=Skipow;1626799]

Wise,
Where in the US are you planning on doing these studies? Will it include all ASIA classifications? Has there been any "non-formal" research on the 3:3:3 vs. 6:6:6 research? I've heard that some researchers feel that locomotive training is more effective by assisted walking, if possible, rather than using a body weighted treadmill (Therastride, Locomat), due to limited side gait mobility in the hips and other things, whats your take on this? What type of locomotive training or exercise regiment is part of this routine? Does this involve other excersizes such as FES and strength workouts? What do you feel would be the difference and requirements from "intensive" locomotive training to "normal" locomotive training?

Thank you!

Skipow,

We were planning to do the studies at Brackenridge Hospital in Austin, TX. Unfortunately, our principal investigator moved to another hospital and we are still raising money for that study. We are still hoping to go ahead with this study but we need to recruit another investigator and raise the funds for the study at Brackenridge.

Yes, there have been many informal studies but what we need are formal controlled studies. Our investigators in Kunming believe that assisted walking on body weight supported treadmill systems is not only ineffective but may teach the body bad habits regarding weight support and balance. Likewise, they do not favor FES. They prefer intensive overground walking over treadmill.

The evidence that treadmill training is superior to overground walking is very limited. Likewise, there is little or no evidence that FES (stimulation of leg muscles) improve unassisted walking to any significant degree. Of course, there are lots of claims by manufacturers of various walking systems, including Locomat and Therastride, but the evidence that these expensive systems have restored walking to people, particularly those with "complete" (ASIA A) spinal cord injury, is very limited.

I have posted on this subject many times, including descriptions of the walking program in Kunming, where they do overground walking with a rolling device that the people lean on and use for partial weight support. They use this walking program extensively in people with acute spinal cord injury. They have published a paper showing that as many as 50% of patients with ASIA A complete spinal cord injuries, who then received a lateral myelotomy within several weeks after injury and participated in this intensive walking training, recover unassisted walking. Since this paper was published, they have treated several hundred patients with similar results.

[*] Zhu H, Feng YP, Young W, You SW, Shen XF, Liu YS and Ju G (2008). Early neurosurgical intervention of spinal cord contusion: an analysis of 30 cases. Chin Med J (Engl) 121: 2473-8. Clinical Center for Spinal Cord Injury, PLA Kunming General Hospital, Kunming,Yunnan 650032, China. BACKGROUND: The incidence of spinal injury with spinal cord contusion is high in developed countries and is now growing in China. Furthermore, spinal cord injury happens mostly in young people who have a long life expectance. A large number of patients thus are wheelchair bound for the rest of their lives. Therefore, spinal cord injury has aroused great concern worldwide. Despite great efforts, recovery from spinal cord injury remains unsatisfactory. Based on the pathology of spinal cord contusion, an idea of early neurosurgical intervention has been formulated in this study. METHODS: A total of 30 patients with "complete" spinal cord injury or classified as American Spinal Injury Association (ASIA)-A were studied. Orthopedic treatment of the injured vertebra (e), internal fixation of the vertebral column, and bilateral laminectomy for epidural decompression were followed directly by neurosurgical management, including separation of the arachnoid adhesion to restore cerebrospinal fluid flow and debridement of the spinal cord necrotic tissue with concomitant intramedullary decompression. Rehabilitation started 17 days after the operation. The final outcome was evaluated after 3 months of rehabilitation. Pearson chi-square analysis was used for statistical analysis. RESULTS: All the patients recovered some ability to walk. The least recovered patients were able to walk with a wheeled weight support and help in stabilizing the weight bearing knee joint (12 cases, 40%). Thirteen patients (43%) were able to walk with a pair of crutches, a stick or without any support. The timing of the operation after injury was important. An optimal operation time window was identified at 4 - 14 days after injury. CONCLUSIONS: Early neurosurgical intervention of spinal cord contusion followed by rehabilitation can significantly improve the locomotion of the patients. It is a new idea of a therapeutic approach for spinal cord contusion and has been proven to be very successful.

Wise.

[ay2012]

Dr. Young,
I have a couple questions that I'm sure will show the layman in me but I was wondering if you could help. You've said that it might be too early, even at six months or a year, to gauge the functional benefits that could occur with these treatments, as the white matter would have to grow up and down the cord. Wouldn't it just be sufficient for growth across the injury site? Also, if we're banking on continued growth for functional return, beyond six months to a year, shouldn't we also be wary of jumping to conclusions regarding safety at these time frames? Or is that just a risk that appears not that great? Thanks as always.

[Barrington314mx]

Dr. Young,
I have a couple questions that I'm sure will show the layman in me but I was wondering if you could help. You've said that it might be too early, even at six months or a year, to gauge the functional benefits that could occur with these treatments, as the white matter would have to grow up and down the cord. Wouldn't it just be sufficient for growth across the injury site? Also, if we're banking on continued growth for functional return, beyond six months to a year, shouldn't we also be wary of jumping to conclusions regarding safety at these time frames? Or is that just a risk that appears not that great? Thanks as always.

This kind of reminded me of my weary thoughts i get when i hear "white matter growing UP the cord to the brain". Sounds scary to me.

[allenstevens]

"I am worried that if we don't have a intensive locomotor training program in the U.S., we will not see any locomotor recovery." Wise, I know a place real close to home where I met you that has a system you speak of Also the question about the baclofen pump any input for that ? Thanks

[havok]

havok,

Our current trials do not rule out penetrating injuries of the spinal cord. We do leave it to the discretion of surgeons to exclude patients whom they think may present difficulties to expose or to transplant. This include lesions that exceed 2 vertebral segments in length and transected spinal cords.

Wise.

Thanks for the reply, I really do appreciate it. Hopefully it is only penetrating. Is there any way to tell if it was transected because when I asked the doctor they couldn't even tell me what happened other than it was a burst fracture. My mom had to tell me about when they did the surgery they said an exploded inward. And also is there any plan for those with "long" injuries? I know mines over 3 segments long. Thanks again, and thanks again for everything your doing

[ay2012]

Thanks for the reply, I really do appreciate it. Hopefully it is only penetrating. Is there any way to tell if it was transected because when I asked the doctor they couldn't even tell me what happened other than it was a burst fracture. My mom had to tell me about when they did the surgery they said an exploded inward. And also is there any plan for those with "long" injuries? I know mines over 3 segments long. Thanks again, and thanks again for everything your doing

Seconded, on the question regarding segmental length. Would applying a potential therapy to a longer injury be the same as that with a higher injury i.e. a separate trial would be needed? I thought these may be treated differently given the concern with higher level of injury was safety, given it could impact breathing function for example.

[comad]

Dr. Wise - 5 questions , please disregard if answered already.
- How many days till we see results published?
- Is US Trial totally jeopardized with 1 doctor / investigator absence?
(aside from that we know for financing issue and FDA approval)
- Trial in Norway on schedule?
- Kunming paper is huge - how to convince world to adopt procedure fast?
- How about Incomplete injuries inclusion in trial or ...?
thanks!

[Wise Young]

Dr. Young,
I have a couple questions that I'm sure will show the layman in me but I was wondering if you could help. You've said that it might be too early, even at six months or a year, to gauge the functional benefits that could occur with these treatments, as the white matter would have to grow up and down the cord. Wouldn't it just be sufficient for growth across the injury site? Also, if we're banking on continued growth for functional return, beyond six months to a year, shouldn't we also be wary of jumping to conclusions regarding safety at these time frames? Or is that just a risk that appears not that great? Thanks as always.

ay2012,

Sensory axons must grow from below the injury site to the brainstem before they can restore function. Motor axons must grow from above the injury site to the lumbosacral spinal cord before they can restore movement. If recovery occurs any faster, it would be because there are existing axons that are crossing the injury site that have sprouted.

Regarding safety, we are looking for complications due to surgery and the transplanted cells. If the cells have grown into a tumor, we expect to see an effect within 6 months. Of course, we would have to wait longer to see any slow effect but we can safely conclude that we see no evidence of any tumor induced or other significant neurological loss associated with the surgery.

Wise.

[Wise Young]

This kind of reminded me of my weary thoughts i get when i hear "white matter growing UP the cord to the brain". Sounds scary to me.

That is what regeneration is. White matter are myelinated spinal tracts. Wise.

[Wise Young]

"I am worried that if we don't have a intensive locomotor training program in the U.S., we will not see any locomotor recovery." Wise, I know a place real close to home where I met you that has a system you speak of Also the question about the baclofen pump any input for that ? Thanks

I don't know (and don't think) that intensive locomotor training alone will help. I am referring to locomotor training after regenerative therapy. Regarding the baclofen pump, I am not sure. We have no experience with transplanting the cells in people with baclofen pump. I would think that we would want to keep it in but to check it regularly to make sure that the spasticity is not declining and the dose can be reduced.

Wise.

[Wise Young]

Dr. Wise - 5 questions , please disregard if answered already.
- How many days till we see results published?
- Is US Trial totally jeopardized with 1 doctor / investigator absence?
(aside from that we know for financing issue and FDA approval)
- Trial in Norway on schedule?
- Kunming paper is huge - how to convince world to adopt procedure fast?
- How about Incomplete injuries inclusion in trial or ...?
thanks!

Comad,

1. The publication will not be for months. We are planning to submit the papers in January. Even in the unlikely case that it is accepted by the first journal that we submit to, it is likely to take 3-4 months. If we have to get it to other journals, it would take 6 months.

2. Are you referring to the Phase 3 trial? If so, the loss of one center would not be a problem. However, in the case of the Phase II trial in Brackenridge, we have to find another principal investigator. Of course, we still have to raise th funds.

3. The trial is Norway is the Phase III trial which is scheduled for Q3 2013. We still have to submit the IND and get the commitment of th Norwegian government to cover the costs. But, yes, I hope and believe that we are on schedule.

4. Kunming paper will be published separately from the Hong Kong paper, which focuses on DTI. The Kunming paper will focus on neurological and locomotor recovery. I myself do not know the results yet. I will find out when I get to Hong Kong shortly after Christmas.

5. I suspect that we will not be including motor incomplete patients in the trials in 2013. The reason is because their inclusion will increase the size of the trial, which we cannot afford at the present.

Wise.