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Comment on the SCINetUSA phase I/II and III trials

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    Comment on the SCINetUSA phase I/II and III trials

    On the July 23rd Summer Open House at the W. M. Keck Center at Rutgers, I tried to talk about a new idea in clinical trials that we are trying to implement in ChinaSCINet and SCINetUSA. Let me expand on the idea here and see if I can get a discussion going.

    As most of you know, clinical trials have one purpose and that is to show that (an) experimental therap(y)ies is safe and effective compared to the best standard therapy. Clinical trials are not to provide people with free access to the latest experimental therapies. Clinical trials are testing therapies that we don't know is better than existing therapies. That's why the therapies are being tested. Nine times out of ten, the therapy turn out to be less safe and effective than existing therapies.

    In order to show that a therapy is effective and safe, the clinical trial must test enough people and compare their response to therapy against a control group, i.e. a group that is receiving the best standard therapy. There is of course variability of responses and changes in neurological status of people with spinal cord injury. Statistical tests must show that the response to the experimental therapy is greater than chance in a control group of people who did not receive the therapy.

    Long experience in clinical trials have shown that people’s attitude towards the therapy can make a big difference in the response to the therapy. Even if the therapy doesn’t work, people often will have a good response to the therapy because they believe, want to believe, and may be desperate to believe that the therapy works. So, many people who have gone overseas for experimental therapies often believe that the therapy works, even though objective assessments of their function shows no change.

    The beneficial effect of therapy due to belief that a therapy works is called a placebo response. Placebo responses are powerful and well-known in medicine. Simply by telling people that they are taking a powerful pain drug, a sugar pill can relieve pain in over 405 of people. Surgery has an even more powerful placebo effect. To rule out placebo responses, clinical trials must have a control group that is treated with a “placebo” and both the doctors and subjects must be “blinded” as to the treatment that they receive.

    By the way, there is an equally powerful negative effect that can come from somebody in authority saying that a condition or treatment is deleterious. Called a nocebo effect, I suspect that probably as many as 50% with incomplete spinal cord injury who could have walked did not because their doctors told them that they will never walk again. In the same way, if you tell subjects in a clinical trial that the therapies they are getting are unlikely to be effective, you can actually have a dampening effect on seeing any positive effect of a therapy.

    In order to see statistically significant treatment effects, it is also essential to choose groups of subjects who have similar conditions and are likely to respond to the therapy in the same way. It is important to keep the condition of the clinical trial as similar as possible for everybody. For example, we don’t have to have people in the experimental treatment group or the placebo treatment group to think that they did not get a therapy that works and therefore will not try hard to walk and recover.

    The SCINetUSA trial wll test the hypothesis that combination treatment with umbilical cord blood mononuclear cells (UCBMC) and lithium is better than UCBMC alone or lithium alone. In order to approve a combination therapy, the FDA require that we show that the combination is better than any of the individual components. Therefore, the trial must include at least lithium alone, UCBMC alone, and the combination UCBMC+lithium. In addition, because we are providing rehabilitation training, we need to have a control group that has only the rehabilitation training, to rule out the possibility that all the recovery resulted from the rehabilitation.

    We chose to limit the age and the spinal cord injury levels that will be tested. For example, subjects must be 18-64. The ASIA neurological levels can be from C5 through T10, inclusive. Only traumatic spinal cord injuries will be considered. We will exclude people with other diseases or head injury. Some of these limits are based on safety concerns and others based on trying to get the comparison groups as similar as possible so that their response to therapy will be similar.

    The trial obviously cannot include everybody in the study. For example, many people were disappointed at our age cutoff. Many are over 64 and others are under 18. The upper neurological level rules out people with high cervical spinal injuries C4 or greater. We will be studying people who are ASIA A. (complete) The lower neurological level rules out people with lower thoracolumbar injuries. The requirement that the injury is traumatic rules out people with atraumatic spinal cord injury, such as stroke, transverse myelitis, tumor, and other conditions.

    So what does being excluded from the main trial mean for people? Will it mean that when the treatment is approved by the FDA, it will not be applicable to people with high quadriplegia or thoracolumbar injuries? Does it mean that the treatment cannot be used for transverse myelitis? Will it mean that the treatment will not be used in children under 18 or adults older than 64? It is true that the FDA approval will usually be given for a therapy for a particular condition. Unless there is evidence to indicate that the treatment is unsafe for certain conditions, the FDA will not usually restrict the therapy for these other conditions.

    If the treatment is shown to be effective and the FDA approves it, it is much easier to expand the indication by doing small trials to show that it is safe and feasible to apply it in these other conditions and showing some efficacy. So, that is the route that we have decided to take in SCINetUSA. We are doing a phase 3 trial that is aimed at the majority population, i.e. traumatic spinal cord injury age 18-64, C5 to T10. We will do a parallel phase 3 trial in China that will include ASIA A, B, and C. In addition, we are planning smaller phase II trials that will test the therapy in children (age 8-17), older adults (age 64-80), high quads (C1-C4), thoracolumbar injures (T11-L1), and non-traumatic spinal cord injuries.

    If the main SCINetUSA phase 3 trial is successful, i.e. shows that the combination therapy is effective adults with chronic traumatic spinal cord injury, the ChinaSCINet phase 3 trial confirms the results and, in addition, shows that the combination therapy is also effective of incomplete injuries, and the phase 2 trials show that it is safe and feasible to carry out the treatments in children, high quads, thoracolumbar injuries, and non-traumatic spinal cord injuries, then it is likely that the treatment will be applied across the board for everybody. That is the approach that we have decided to take.

    Wise.

    #2
    Sounds like a solid game plan, statistically, Dr. Young. I wish you (and consequently all of us) great luck!
    No one ever became unsuccessful by helping others out

    Comment


      #3
      "...then it is likely that the treatment will be applied across the board for everybody. That is the approach that we have decided to take."
      Wise.[/QUOTE]
      Godspeed.

      Comment


        #4
        Thanks for the thorough explanation Dr. Young. I admit, being a C3 quad with phrenic nerve stimulators, I was a bit bummed when I first read what the qualifications for the study were. But now, I know that it's just not my turn yet.

        Chuck

        Comment


          #5
          Many thx dr Wise for the time and effort to cure us.
          Can I ask you:
          - how many ppl will get the combination and how many will be in the placebo group?
          - ChinaSCINet phase III will happen is same time as SCINetUSA? The results from ChinaSCINet are valid for FDA approval?

          "...... probably as many as 50% with incomplete spinal cord injury who could have walked did not because their doctors told them that they will never walk again. In the same way, if you tell subjects in a clinical trial that the therapies they are getting are unlikely to be effective, you can actually have a dampening effect on seeing any positive effect of a therapy."

          That's why some treatments are effective on mouses ONLY? Let's find a solution for nocebo effect too.
          Last edited by cypresss; 26 Jul 2009, 7:20 AM.
          This signature left intentionally blank.

          Comment


            #6
            Dr wise
            this is great news can you tell us a time scale when the results will be back 1year to 5 or will it be more or can you tell us what they or ready know
            AS I SIT HERE IN MY CHAIR . I LOOK OUT UPON THE GROUND .I WONDER WILL I EVER GET UP AND WALK A ROUND ??


            http://justadollarplease.org

            Comment


              #7
              Originally posted by skeaman View Post
              Dr wise
              this is great news can you tell us a time scale when the results will be back 1year to 5 or will it be more or can you tell us what they or ready know
              Skeaman, I think wise had posted in some thread that Scinet will start it in 2010 after patient selection and tying up funding and all. It will take a year for the phase III after which depending on the result, they will submit it to FDA in 2011.

              Comment


                #8
                Dr. Wise,

                Comment


                  #9
                  How is are the cells/lithium to be administered? Intrvenous,, into the spinal fluid,, above/below injury site? And how long post injury is the criteria to be?

                  I'm sorry if these questions have been answered before in other threads, but I'm new here and thought going with "todays posts" would be less of an imposition on others.
                  ed

                  Comment


                    #10
                    thanks for that
                    so let me get this right hopeful phase 111 is over and result is good it than goes to FDA in 2011 do you know how long will they will sit on it be four it comes to us point is it is years keep going buy the good thing is it is start and if it was to come that quick it would stop ones going over seas i do hope it is not all talk it would be nice for them to keep us up dated what is going on so it can gave us hope
                    AS I SIT HERE IN MY CHAIR . I LOOK OUT UPON THE GROUND .I WONDER WILL I EVER GET UP AND WALK A ROUND ??


                    http://justadollarplease.org

                    Comment


                      #11
                      Prof. Young I find that what you are explaining is very rational and I agree with that approach.

                      I belive also that many people with SCI will find it a little discouraging as many of us probably would like to hear that a therapy restored near normal function in chronic rats and that tomorrow clinical trials are going to start.
                      Others would like just to make sure that the therapy that is going to be tested is "the one" out of ten that works.
                      It is an emotional game we can't avoid. Emotion (from latin "to move") is what drive most people actions.
                      I guess many of us need to be educated also on our emotions to accept the cure process and work for it.

                      Paolo
                      In God we trust; all others bring data. - Edwards Deming

                      Comment


                        #12
                        Dr. Young,

                        Thank you for your articulate and pragmatic approach. One question I have is whether or not hand function will be assessed. I understand that locomotion training is provided and that locomotive therapy has clear criteria to define progress. Will there be any training e.g arm bike, grasp e-stim, pushup-like assessment?

                        A concern for many living with quadriplegia is as you know hand function. My physician of rehabilitative medicine told me that hand function is harder to recover then locomotion. I'm not sure why this is so. His opinion was based upon years of experience. Is there any scientific or neurological explanation for why arm and hand function would be harder to restore?

                        Thank you again for your time and Herculean efforts.

                        Comment


                          #13
                          Originally posted by Chaz19 View Post
                          Dr. Young,

                          Thank you for your articulate and pragmatic approach. One question I have is whether or not hand function will be assessed. I understand that locomotion training is provided and that locomotive therapy has clear criteria to define progress. Will there be any training e.g arm bike, grasp e-stim, pushup-like assessment?

                          A concern for many living with quadriplegia is as you know hand function. My physician of rehabilitative medicine told me that hand function is harder to recover then locomotion. I'm not sure why this is so. His opinion was based upon years of experience. Is there any scientific or neurological explanation for why arm and hand function would be harder to restore?

                          Thank you again for your time and Herculean efforts.
                          Chaz,

                          As explained, the reason why we have to focus on the legs is because this trial will include both thoracic and cervical spinal cord injury and walking is the only standardized outcome that is common between paraplegics and quadriplegics. We will be getting overall motor scores of all the subjects at 6 weeks, 6 months, and a year after injury. Half of the ASIA motor scores are related to the upper limbs. So, we will have a rough measure of hand function. The primary outcome measure of the study will be the change in motor scores.

                          I agree with your rehabilitation doctor that walking will be easier to restore than hand function. There are three bodies of evidence that support this view.

                          The first is the so-called central cord syndrome. As you may know, this is a condition where the hand function are worse than the legs. It is called a central cord syndrome because people use to speculate that the damage is to the central part of the spinal cord where presumably the gray matter for the hands are located. More recent work by Dick Bunge, et al. suggesting that central cord syndrome is not as much damage to the central gray matter as it is the lateral column white matter. The point is that walking does not require as much white matter as hand function.

                          The second is the discovery of the central pattern generator or CPG in humans. While the CPG has long been known to be present in animals, it was not demonstrated in humans until about the 1990's. The CPG can be activated by relatively few descending axons. It then can execute programmed movements such as walking, running, hopping, skipping, trotting, etc.

                          The third is finding that over 90% of people who have "incomplete" spinal cord injury are able to recover independent walking. This is really quite a finding and one that one would not expect unless one only needs few axons to achieve walking.

                          Wise.

                          Comment


                            #14
                            Originally posted by Wise Young View Post
                            thoracolumbar injures (T11-L1), and non-traumatic spinal cord injuries.
                            Marvelous idea. This means us, Lyniffer.

                            Comment


                              #15
                              Originally posted by skeaman View Post
                              thanks for that
                              so let me get this right hopeful phase 111 is over and result is good it than goes to FDA in 2011 do you know how long will they will sit on it be four it comes to us point is it is years keep going buy the good thing is it is start and if it was to come that quick it would stop ones going over seas i do hope it is not all talk it would be nice for them to keep us up dated what is going on so it can gave us hope
                              Skeaman, the requirements are two phase III trials that the FDA agrees will show efficacy of the therapy. We are therefore doing two trials. One in China and one in the U.S. We will be registering both trials with the U.S. FDA.

                              One has to discuss the trials with the FDA to make sure that the outcome measures fit with what that FDA believes are reasonable. It is possible that the FDA may require a functional outcome. It is also possible that they would want us to compare the treatment group against what they consider to be appropriate controls.

                              How long it will take for approval depends on the results. If the results are what the FDA agrees would show efficacy and the treated groups meet the criteria for efficacy, the FDA may approve pretty quickly but an approval requires several other things besides a clinical trial to show efficacy.

                              The FDA will want to ensure that the product (i.e. cells is what we say that it is, inspect the manufacturing process, and determine that it meets GMP or good manufacturing practices). This should be reasonably quick because the umbilical cord blood cells are being provided by a company that is already highly certified for cell transplantation.

                              It is hard to tell. If everything is in order, an approval within a year after the clinical trial could happen.

                              Wise.

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