ChinaSCINet Update

[Lyerly]

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.

We will not be able to see any of the information I results until it is officially published?

What is the cost per patient? What is the total that needs to be raised for ASIA A only? What would it take to see a few C's included? Dollar wise?

[lunasicc42]

We will not be able to see any of the information I results until it is officially published?

What is the cost per patient? What is the total that needs to be raised for ASIA A only? What would it take to see a few C's included? Dollar wise?

Yes, I was under the impression that we would hear results sometime this month... Is that correct?

[Barrington314mx]

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

But what stops them from growing? Or how do they know when to stop? Maybe i watch too many weird movies. I get a picture of over grown ivy taking over my brain.

[stacyd]

dr wise
i though axons only need to connect on each side of the lesion,sensory or motor to establish function?

[ay2012]

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.

Dr. Young,
Thanks for the response and sorry to press the issue, but could you provide some reasoning or even just literature as to why you would assume that the six month time frame would be sufficient to tell if a tumor would grow. I'm sure you've thought that through, but its the most common response I hear from people, even people in the rehab community, top physiatrists, heck even my main doctors in acute care as to why one should be weary for participating in trials and stem cell therapies more generally. Obviously these people aren't at the forefront of the research but it'd be nice to have a response to them.

[Wise Young]

We will not be able to see any of the information I results until it is officially published?

What is the cost per patient? What is the total that needs to be raised for ASIA A only? What would it take to see a few C's included? Dollar wise?

Lyerly,

I have not yet decided whether or not to release the 6-month data. I have not seen the data yet but I am not sure that pre-release of the data serves any purpose.

Regarding cost per patient, I have indicated several times now that we estimate the cost to be $100,000 per subject. So, a 20-subject Phase II study plus organization and insurance costs adds up to about $2.1 million. A 120-subject Phase III study would cost about $12 million. We may achieve some savings here and there.

One cannot not just include "a few C's" in a clinical trial, just for curiosity sake. If we include ASIA C subjects in a phase III trial, we would need to include sufficient subjects to determine whether outcome of A's differ significantly from C's. Since C's are more variable than A's, we will need more subjects than just doubling the number of subjects. Thus, adding C's to the U.S. phase III trial would more than double the cost of the trial. We were originally planning to include B's and C's in the ChinaSCINet trial because the cost of trials is about one fifth of the cost in the U.S. I had earlier estimated that inclusion of A, B, and C's in China would require a study of about 400 subjects. To save money, we are considering studying only 120 ASIA A subjects in China as well.

Wise.

[Wise Young]

Dr. Young,
Thanks for the response and sorry to press the issue, but could you provide some reasoning or even just literature as to why you would assume that the six month time frame would be sufficient to tell if a tumor would grow. I'm sure you've thought that through, but its the most common response I hear from people, even people in the rehab community, top physiatrists, heck even my main doctors in acute care as to why one should be weary for participating in trials and stem cell therapies more generally. Obviously these people aren't at the forefront of the research but it'd be nice to have a response to them.

ay2012,

Umbilical cord blood cells have been transplanted into many thousands of people over the past 20 years. To my knowledge, no case of tumor of the transplanted umbilical cord blood cells has ever been reported. The cells that we are using have not been genetically modified, expanded, or altered.

In our trials, we have transplanted umbilical cord blood cells into 41 subjects. Several of the subjects are a year and half after injury. Over 10 of the subjects are more than one year after transplantation. All are over 6 months. If we do not see any safety issues at this point, there are unlikely to be any. I hope that the FDA will accept our data.

The risk is not zero, of course. But, the risk is very low. Are you sure you want to insist on more stringent safety criteria, like a year or two? If so, this guarantees delays of 2 or more years between trials.

Wise.

[Wise Young]

dr wise
i though axons only need to connect on each side of the lesion,sensory or motor to establish function?

Stacyd,

Let me explain it first in words and then with a diagram. Two sensory tracts bring sensory information to the brain. One is situated in the posterior columns of the spinal cord and makes synapses (connections) with neurons in the brain stem called nucleus gracilis (for sensations coming from the legs) and nucleus cuneatus) for sensations coming from the arms). These nuclei in turn sends axons to the thalamus which is at the center of the brain and distributes the information to the cortex. The second tract is located in the lateral column and is called the spinothalamic tract. It travels all the way from below the injury site to the thalamus.

Several motor tracts carry motor information for movement. One is called corticospinal tract, carrying axons directly from neurons in the cortex to the lower spinal cord. Others include rubrospinal tract (which runs from the red nucleus in the midbrain to the spinal cord below the injury site), the cerebellospinal tract (which runs from the cerebellum to the lower spinal cord), the vestibulospinal and reticulospinal tract (which runs from the brainstem to the lower spinal cord), and the propriospinal tract (which runs from the upper spinal cord to the lower spinal cord). These motor axons must grow from above the injury site to the lower spinal cord.

The central pattern generator (CPG) is located in the upper portion of the lumbosacral spinal cord (where the L2 cord is). Axons that are growing down the spinal cord are likely to get to the CPG first before they reach the motoneurons that operate the legs. Activation of the CPG can activate the legs to do stepping. In the picture below, I show the sensory tracts (red) and the motor tracts (blue). The spinal cord injury site is depicted by the grayish red area. The solid lines indicate where the axons are still intact below (sensory) and above (motor) the injury site. The dotted line indicates the path that the axons must grow.

Wise.

[t8burst]

Wise, that asymmetry is interesting. If I read that correctly a person with a C level injury would regain sensation below their injury site before movement and the reverse for people L injuries. Someone like me (T8) would regain them about the same time period. Is that correct?

[Wise Young]

Wise, that asymmetry is interesting. If I read that correctly a person with a C level injury would regain sensation below their injury site before movement and the reverse for people L injuries. Someone like me (T8) would regain them about the same time period. Is that correct?

Yes. For example, Christopher Reeve regained sensation in 3/4 of his body since by about 2 years. He had a C1/2 injury.

Somebody with a mid-thoracic spinal cord injury (like you) should get motor function back if the tracts are regenerating.

Wise.

[stacyd]

Dr Wise Young
Thank you! I have a better understanding now.

[ay2012]

Lyerly,

I have not yet decided whether or not to release the 6-month data. I have not seen the data yet but I am not sure that pre-release of the data serves any purpose.

Regarding cost per patient, I have indicated several times now that we estimate the cost to be $100,000 per subject. So, a 20-subject Phase II study plus organization and insurance costs adds up to about $2.1 million. A 120-subject Phase III study would cost about $12 million. We may achieve some savings here and there.

One cannot not just include "a few C's" in a clinical trial, just for curiosity sake. If we include ASIA C subjects in a phase III trial, we would need to include sufficient subjects to determine whether outcome of A's differ significantly from C's. Since C's are more variable than A's, we will need more subjects than just doubling the number of subjects. Thus, adding C's to the U.S. phase III trial would more than double the cost of the trial. We were originally planning to include B's and C's in the ChinaSCINet trial because the cost of trials is about one fifth of the cost in the U.S. I had earlier estimated that inclusion of A, B, and C's in China would require a study of about 400 subjects. To save money, we are considering studying only 120 ASIA A subjects in China as well.

Wise.

Sorry, does this mean there won't even be an update on the trials after you take a look at this data (as was originally suggested....as in you won't broadly comment on the results) or that the detailed data won't be released (which I'm assuming it wouldn't given it'll be pending publication)?

[Wise Young]

Sorry, does this mean there won't even be an update on the trials after you take a look at this data (as was originally suggested....as in you won't broadly comment on the results) or that the detailed data won't be released (which I'm assuming it wouldn't given it'll be pending publication)?

As I said, I have not yet decided. Wise.

[ay2012]

Most clinical trials do not release data until the trials have ended. As a service to the community, we are releasing interim analyses of data when they become available. For example, we released 6-week safety data of the trial this past summer as soon as they were available. Analyses of 6 month followup data will not be available until all the 6-month data has been collected. Yes, some one-year followup data are available from several of the patients who were transplanted before October 2011 but these will not be released until all the one-year data has been collected and analyzed. We do not yet have two-year followup data on any patient.

Wise.

Was your mind changed because of the backlash/questioning that came when you provided the last personal observations? The fact that you keep us in the loop and the access you give of yourself to our questions and concerns is, as you note, not common....but its also a reason, among others, why so many throw our support behind your work.

[allenstevens]

As I said, I have not yet decided. Wise.

Really ?