Spinal Cord Injury Network USA (SCINetUSA)

[ricanstruction]

Art Show fundraiser--any other artists in the house?

I just posted some of my paintings from art therapy at Mount Sinai and currently working on some canvas pieces for a proposed art show to fund the SCINet. Any other artists interested? Jim, Can we get a date for the Keck center so we can start crankin out some posters?

[ricanstruction]

PS--you can view these paintings here: http://www.facebook.com/album.php?ai...0&l=614d6feac3

[Jim]

Looks like we are going to have a art show/sale at the Open House on Thursday July 23.
Anyone interested in submitting artwork?

[ricanstruction]

Woohoo! How are we going to advertise this, Jim? I can print out a few posters for Beth abe, Mount Sinai and maybe a couple other facilities. Other than that, web will have to do or organizations can print their own posters? Have you contacted North center yet or should I? A month is just around the corner, we need to get crackin!

[ricanstruction]

Specific place at Keck Center? Time? Phone or email for further info?

[Sue Pendleton]

Hello Jim,

I don't think I can make it, but I am trying to force Leif to do so, since he has a lot to say I am courious to see if he has the balls to go to W2W an say there in person what he writes.

Paolo

I'll be happy to ask Leif's questions for him. With both Wise and Doug Kerr there I'd like some answers about the exclusion of non-traumatic injuries. I may have funded research that wound up excluding atraumatics because until very recently I had never heard anything about different sized myelin cells.

[Wise Young]

I'll be happy to ask Leif's questions for him. With both Wise and Doug Kerr there I'd like some answers about the exclusion of non-traumatic injuries. I may have funded research that wound up excluding atraumatics because until very recently I had never heard anything about different sized myelin cells.

Sue, perhaps I can start the discussion now because so that we don't spend a lot of time sorting through misunderstandings.

First, let me discuss the concept of clinical trials and power analysis. This is not just a matter of including or excluding a condition. Clinical trials have one purpose and that is to asess the efficacy of a treatment for a given condition. In order to establish the appropriate number of subjects that would be tested for a clinical trial, you have to study a control group of such patients in order to find out the variability of the group. From the standard deviation of the your chosen primary outcome measure, you carry out a power analysis. A power analysis is a simple test which assumes a certain expected change in outcome (e.g. 5% change of ASIA motor score) that can be detected with a given probability (e.g. p<0.05). From NASCIS (the trials that tested methylprednisolone) and our own observational trials in China, we have determined that 60 subjects per treatment-injury group would provide sufficient "power" to detect a 10% change in ASIA motor score. Therefore, we designed a clinical trial that has 60 subjects per treatment-injury group. We have three treatment groups: lithium, umbilical cord blood mononuclear cell (UCBMC) transplants, and UCBMC + lithium. With 60 subjects per treatment group, this adds up to 180 subjects in the clinical trial. Since we can have only one injury group, we chose to test only subjects with ASIA A. Because the outcomes of ASIA A and ASIA C are so different, inclusion of the latter into the treatment groups will increase the variability of the group so that we need much more than 60 subjects to detect a 10% treatment effect. That is why we chose to test only subjects with ASIA A traumatic spinal cord injury. A 180-subject trial will cost us about $20 million to carry out.

In ChinaSCINet, we are planning to study 400 subjects in the phase 3. This will allow us to have separate six treatment-injury groups (i.e. the three treatments divided into ASIA A and ASIA B/C). This is because a trial in China will be less expensive than in the United States, probably a fifth of the cost that we are looking at in the U.S.A. At the present, we are doing phase 1 and 2 trials with lithium, UCBMC, and UCBMC + lithium on only subjects with chronic traumatic spinal cord injury. We are also choosing to restrict the age of the patients because our data does not encompass children or very old adults.

The reason why we cannot include atraumatic spinal cord injury in the planned SCINETUSA phase 3 trial is because we don't have any data concerning the variability of the atraumatic spinal cord injury and its response to therapy. If we want to do that, we need to carry out a separate phase 1/2 trial that which assesses the safety, feasibility, and possible efficacy of the treatment. The trial should show us that the treatment is safe and feasible, as well as provide the power analysis for the design of a phase 3 clinical trial for atraumatic spinal cord injury. If the trial shows a dramatic treatment effect, then of course this probably would be sufficient to justify a larger trial that would justify approval of the label of the therapy.

Wise.

[Sue Pendleton]

The reason why we cannot include atraumatic spinal cord injury in the planned SCINETUSA phase 3 trial is because we don't have any data concerning the variability of the atraumatic spinal cord injury and its response to therapy.

What if another source had this information? More specifically broken down to ASIA A, B and all other and again by cause? Would the data be sufficient or would a hospital/rehab group need to join SCINetUS for their patients to be treated? Just out of curiosity (and that the stuff is cheap, easily gotten and when monitored rather safe), will the lithium alone results be released early if it appears to create return or adds neuroprotective action to any other modalities or drugs used? I know several Americans treated in the early 1990's in places like the Ivory Coast, Ghana and Senegal who recovered a lot of function, including one cervical central cord who is independent, after receiving methylprednisolone as it is cheap enough in Africa and is normally the branded Solumedrol. Lithium alone could possibly help some of the chonically injured in the developing world regain some function while not causing problems with their balance of payments due to its low cost. Monitoring costs are also low as labor is cheap and I understand that the testing is not extensive but limited to a few items on chem panel.

And did I miss something about the Canadians and Mexicans pulling out of NASCINet?

[Wise Young]

What if another source had this information? More specifically broken down to ASIA A, B and all other and again by cause?

• Sue, I have been in the field for a long time and I don't know of any such study of transverse myelitis or ischemic spinal cord injury. As you know, both are extremely variable conditions. Only small series have been reported in the past. We not only require ASIA classification but detailed motor and sensory scores obtained by a reliable group. Also, as I have explained before, ischemic spinal cord injury may differ from traumatic spinal cord injury in the type of white matter damage and extent of gray matter injury in the lower spinal cord. I am very much in favor of doing a separate trial for TM and ischemic spinal cord injury but believe that we cannot justify including these two conditions in a trial of traumatic spinal cord injury.

Would the data be sufficient or would a hospital/rehab group need to join SCINetUS for their patients to be treated?

• I don't understand your question. Perhaps I have buried it in long posts that I have made but I have said that we would need to do a separate phase 2 trial for ischemic spinal cord injury and transverse myelitis. For example, I have spoken to Doug Kerr about the possibility of doing a separate trial for TM. SCINetUSA is a clinical trial network and will be helping organize such trials as best as it can. Before a clinical trial can be carried out, one must identify investigators, sites, and develop protocols.

Just out of curiosity (and that the stuff is cheap, easily gotten and when monitored rather safe), will the lithium alone results be released early if it appears to create return or adds neuroprotective action to any other modalities or drugs used? I know several Americans treated in the early 1990's in places like the Ivory Coast, Ghana and Senegal who recovered a lot of function, including one cervical central cord who is independent, after receiving methylprednisolone as it is cheap enough in Africa and is normally the branded Solumedrol. Lithium alone could possibly help some of the chonically injured in the developing world regain some function while not causing problems with their balance of payments due to its low cost. Monitoring costs are also low as labor is cheap and I understand that the testing is not extensive but limited to a few items on chem panel.

• That is why we are doing a placebo-controlled lithium trial now. If we find significant improvement in people with chronic spinal cord injury after lithium treatment, there is no force in the world strong enough nor any reason to prevent the drug from being used by many patients. But, we should not and must not encourage the use of the drug before the data becomes available. The drug is not innocuous and I have already heard enough stories to make my toes curl in dread. There are a lot of people who have no idea what they are doing and are taking lithium. This includes doctors. It is possible to damage your brain if you take too much lithium for too long. The dose needs to be titrated to achieve specific serum levels. People SHOULD NOT be taking this drug without supervision by an experienced physician.

And did I miss something about the Canadians and Mexicans pulling out of NASCINet?

• Canadians and Mexicans did not pull out. We are just beginning discussions with one group in Mexico and we have not yet had any discussions with any Canadian group.

[jhorn4012]

I've tried to post to this site 3 times. Why can't other centers work together such as Baylor, Dallas and Brackenridge Hospital? Baylor Institute of Rehab has a meeting coming up in July 14th topic: Current Spinal Cord Injury
Research at 6:30pm(contact: Dr. Warren at 214 820-9315 or email: annmariw@baylorhealth.edu. I'm going to ask that question if they are considering doing clinical trials in these areas that have been discussed on this site. I would like to see others such as ASIA B - through whatever incompletes also given the chance to be considered for clinical trials.

[Wise Young]

For those who may not yet be inculcated in clinical trials, let me try to explain the principles of clinical trial design.

Clinical trials have one main purpose and that is to ascertain the safety and efficacy of therapies. Subjects who participate in clinical trials should understand that they are performing a service for others in taking the risk of therapies that have not yet been sufficiently tested to ensure safety and efficacy of the therapy. Clinical trials are not intended to provide people access to non-approved therapies.

In order to ascertain the safety and efficacy of a therapy, a clinical trial must compare subjects who are treated with the experimental therapy against subjects who are treated with some kind of control therapy. For this comparison to be valid, enough subjects must be included in the treated and control groups so that statistically significant data can be ontained.

To estimate the number of subjects that are required in each group to show statistical significance, one must know the variability of the condition. If the condition is very variable, one needs many more subjects in the treatment and control groups to detect a difference that is statistically significant. In general, most clinical trials adopt the criterionof p<0.05 for significance, meaning that the there is only a 5% chance that an observed difference is due to chance.

In addition, one must assume an expected difference between the treatment and control groups. When one calculates the number of subjects that are needed for a clinical trial, one must decide what the expected treatment effect should be. For example, let us assume that we are expecting a 10 point difference in motor score. The ASIA motor score is 100 points. We know from previous studies (NASCIS, for example) that 60 subjects per group is sufficient to detect a 10-point difference in motor score with a p-value of 0.05 in patients with traumatic spinal cord injury.

In the US103, the clinical trial that we are planning to compare lithium, umbilical cord blood mononuclear cells (UCBMC), and UCBMC plus lithium, we are planning to have about 60 subjects per group. This is a total of 180 subjects. Because we believe that people under age 18 and over 64 may recover differently, we are limiting the trial to adults between ages 18-64. We are also limiting the trial to C5 and T10 inclusive because we are concerned with transplanting cells into spinal cord at C4 and because injuries below T10 may compromise gray matter. We are restricting the trial to those people who are able to stand (in a standing frame) for at least one hour per day because we are intending to encourage all the subjects to engage in intensive locomotor training. Finally, all the subjects should be stable neurological neurologically (neither improving or deteriorating) over a six month period.

All these inclusion and exclusion criteria is to ensure that we have a reasonably uniform group of patients in each of the treatment groups. These restrictions do not mean that we believe that these therapies are ineffective in the other patients. They are intended to maximize the chances the the clinical trial will show a positive result with the least number of complications. The first and most important goal of the clinical trial is ascertain whether the treatment is safe and effective.

Please note that a successful clinical trial is one that shows that a treatment is either effective or ineffective. A trial "fails" if it provides inconclusive data. After spending all the time, money, and risk to subjects, if we don't know whether a therapy works or does not work, the trial has "failed". If the trial shows conclusively that umbilical cord blood mononuclear cells plus lithium combination therapy is ineffective, it is a successful trial.
That is what the trial shows and we should go on to other treatments or find a combination that is better.

So, what happens to people who have conditions that fall outside of the inclusion and exclusion criteria for the trials. What we are offering are small phase 2 trials of 20 subjects to assess safety and possibly efficacy. These trials are open label trials and are intended to establish the feasibility and possible efficacy of the therapy in small groups of patients under similar conditions. So, for example, we are planning trials to look at umbilical cord blood plus lithium in children between ages 8-17 and older adults who are 64 to 80 years old.

Likewise, we are discussing and planning trials to examine people who are high spinal cord injury (C4 or higher) and lower spinal cord injury (T11 or lower). Thse will require difference protocols and different outcome measures. Below, we have been having a discussion of including subjects who have ischemic spinal cord injury or transverse myelitis. I think that we would need to test these subjects under a separate phase 2 trial. If that trials shows that the treatment is safe and possibly efficacious, we would then go ahead to do a larger controlled trial. By the way, it is possible that if the results are convincing and the main trial on traumatic spinal cord injury shows that the treatment is safe and effective, it is entirely possile that we will not need to do a phase 3 trial in order to extend the use of the treatment to ischemic spinal cord injury and transverse myelitis.

Even very experienced people in our community are getting confused with this issue and I would appreciate questions to help me understand what people are confused about.

Wise.

[Wise Young]

I've tried to post to this site 3 times. Why can't other centers work together such as Baylor, Dallas and Brackenridge Hospital? Baylor Institute of Rehab has a meeting coming up in July 14th topic: Current Spinal Cord Injury
Research at 6:30pm(contact: Dr. Warren at 214 820-9315 or email: annmariw@baylorhealth.edu. I'm going to ask that question if they are considering doing clinical trials in these areas that have been discussed on this site. I would like to see others such as ASIA B - through whatever incompletes also given the chance to be considered for clinical trials.

jhorn,

It is not a matter of centers working together. Each center that joins the network costs us substantially to train and include. Just costs of transporting and housing two investigators from each of ten centers, for example, costs us over $20,000 per monthly investigator meeting.

We have not been aggressively recruiting other centers because we may not need so many center and we cannot afford to have a larger network. I estimate that the inclusion of each center costs the network about $100,000 per year to train and coordinate. Of course, if Baylor is interested in joining the network, we would not turn them down.

Not all centers in a network may be involved in every clinical trial that a network does. Eventually SCINetUSA will be substantially bigger than 10 centers. ChinaSCINet has about 24 centers right now. However, for the specific clinical trial, we may not need more than ten centers.

Wise.

[Sue Pendleton]

• Sue, I have been in the field for a long time and I don't know of any such study of transverse myelitis or ischemic spinal cord injury. As you know, both are extremely variable conditions. Only small series have been reported in the past. We not only require ASIA classification but detailed motor and sensory scores obtained by a reliable group. Also, as I have explained before, ischemic spinal cord injury may differ from traumatic spinal cord injury in the type of white matter damage and extent of gray matter injury in the lower spinal cord. I am very much in favor of doing a separate trial for TM and ischemic spinal cord injury but believe that we cannot justify including these two conditions in a trial of traumatic spinal cord injury.

Everyone who joins the TMA, for those interested it's free, receives a 40 page history to fill out. These are compiled by the president Sandy Siegel who gets great use of his statistics by fire courses needed for his PhD in another field. For new injuries the history is easy to fill out and I know many doctors help at this point. For those who join years after an injury memory or getting copies of records is often used. Many who are originally diagnosed as TM have that change, as you know, to Devics, ON, MS or even to GBS or infarcts although the last two are rare as they behave differently from the beginning. But they do not toss histories solely because they are not TM. The histories, while not a study, have been able to pinpoint a 40 square mile area of Texas I wouldn't want to live in for fear of TM on top of the stroke. There are several high case areas around the world that have been located but not why they are high case. We're not talking the MS frequency that increases as you head away from the Equator.

• I don't understand your question. Perhaps I have buried it in long posts that I have made but I have said that we would need to do a separate phase 2 trial for ischemic spinal cord injury and transverse myelitis. For example, I have spoken to Doug Kerr about the possibility of doing a separate trial for TM. SCINetUSA is a clinical trial network and will be helping organize such trials as best as it can. Before a clinical trial can be carried out, one must identify investigators, sites, and develop protocols.

Then I'll assume questions for Dr Kerr should be aimed at the specific type of stem cells he's been working on for those with atraumatic injuries. I have the feeling his group will be more interested in the specifics of non-traumatic injuries and will have different age groups also as a significant number of ventilator dependent patients are 18 to 24 months old when diagnosed. And those of us who fall into the rarer injuries including central cord syndrome, well, if we wait for the full set of trials for traumatic injuries and then again for a phase 1/2 for TM, ischemia, etc., then we're looking at being over the main age groups for traumatics. I personally can't wait that many years and then all the time you've said over and over that it takes for new cells to grow. I believe nervous system cells grow at about the same speed as hair.

[quote] • That is why we are doing a placebo-controlled lithium trial now. If we find significant improvement in people with chronic spinal cord injury after lithium treatment, there is no force in the world strong enough nor any reason to prevent the drug from being used by many patients. But, we should not and must not encourage the use of the drug before the data becomes available. The drug is not innocuous and I have already heard enough stories to make my toes curl in dread. There are a lot of people who have no idea what they are doing and are taking lithium. This includes doctors. It is possible to damage your brain if you take too much lithium for too long. The dose needs to be titrated to achieve specific serum levels. People SHOULD NOT be taking this drug without supervision by an experienced physician. [/unquote]

I didn't suggest using lithium until the first trials show improvement or lack of. If there is improvement in phase 2s then serum levels should be identified and for various groups: male, female, age, by body weight because even considering differences in sexes, weights and proportion of lean to fat is different in the developed versus third world population. Brain damage? When I first asked my neurologist about it he turned around from his notes and bluntly said "great stuff if you want to destroy your kidneys". I think a protocol for the off label use, IF it improves function/sensation, of lithium should be widely distributed so doctors do know how to use it for SCI as they are currently guesstimating for ALS and how it differs from the dosing used for mental disorders which is what most doctors are familiar with in its use. I merely suggested that why should people who live out of, or in, the reach of the FDA wait decades if, by itself, it actually can improve peoples lives when properly administered.

• Canadians and Mexicans did not pull out. We are just beginning discussions with one group in Mexico and we have not yet had any discussions with any Canadian group.

Then why the change of name from NASCINet to SCINetUSA? Or did I miss a post in this thread or another?

[Rollin Rick]

Dr. Young,

You are discussing about a separate trial for C4 and higher in post # 146. Now take someone like myself where I have C4 on the left side, C5 on the right, what type of trial would be considered for people with this type of injury?

Rick.

[ChuckFoss]

Hi Jim, I've been away from CareCure for a while, so I'm just now reading about SCINetUSA and the fund raising efforts. This is GREAT news. I've been following the progress of ChineSCINet and know they've made solid progress. A big THANKS to you and Dr. Young for making it happen here.

I like the concept behind justadollarplease.org and think the site is well done. However, I think 2 things are missing: a PayPal option to make it even easier for folks to contribute, and some specifics. What I mean is that there is little detail there. I think the site would benefit from having an "About Us" button at the top for people to click on. This button would give some background on the organization, a profile of Dr. Young and specifics about the trial.
I think people will be more apt to donate if they feel informed about where their money is going.

Again, thank you for all you've done!