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    Cethrin Clinical Trial

    Is it being used on chronic incomplete cervical injuries?
    I read on forum site at christopherreeves that the trial was
    showing improvement on C injuries and
    not so much for thoriac injuries. Any info would be helpful.
    Especially if it would help control spasms.
    Aggie Mom 2007

    Cethrin "appears promising and safe" for treatment of acute cervical spinal cord injuries

    Michael Fehlings

    Speaking at the recent World Spine meeting in Istanbul, was Dr Michael Fehlings, Medical Director of the Krembil Neuroscience Centre, Toronto Western Hospital and Professor of Neurosurgery, University of Toronto, Canada, who presented the results of the Cethrin Phase 1/11a prospective clinical trial.

    Fehlings began his discussion by explaining the mechanisms of acute traumatic spinal cord injury, followed by outlining Cethrin and Cethrin delivery. Cethrin is a Rho inhibitor that consists of BA-210 (the active ingredient) and is combined with an approved fibrin sealant that is administered directly at the site of injury during surgery to repair spinal cord injuries.

    In previous animal studies, Cethrin has demonstrated that it helps in the repair of damaged central nervous system (CNS) neurons. Some of the beneficial actions of Cethrin application following acute spinal cord injury are as follows:
    Inhibition and even reversal of abnormal Rho GTPase activation after just a single dose.

    Significant reduction of apoptosis at the site of injury.

    Promotion of axonal regeneration.

    Functional recovery in animals after spinal cord injury, as measured by hind-limb movements using the Basso, Beattie and Bresnahan (BBB) locomotor rating scale.

    The study sites were held in nine cities in the US and Canada, and the primary aim was to assess the safety and tolerability of the drug. The secondary endpoint was to examine the pharmacokinetic profile of Cethrin in blood and the neurological outcome, using the American Spinal Cord Injury Association (ASIA) scores.

    The study took place over six weeks, with a 12-month follow-up, and dose escalations of a single application of Cethrin on dura mater, ranged between 0.3mg, 1.0mg, 3.0mg, and 6.0mg for thoracic and cervical patients. Thirty-seven patients were enrolled in the study, who were divided into the following catergories:

    Safety overview
    Following this, Fehlings reported that from the results, there were no drug related serious adverse events - one patient died or acute respiratory distress syndrome (ARDS) in the first three weeks after spinal cord injury (SCI), and one patient was diagnosed with a cerebral glioma (present after retrospective review of initial CT brain). There were no dose dependent serious adverse events and low systemic exposure (PK parameters). Overall, Cethrin application appeared safe in terms of normal parameters, explained Fehlings, such as vitals, clinical labs and neurological exams (MRI and ASIA). Other events included one patient who had prolonged hospitalisation due to fever, one patient with a thoracic injury who deteriorated by five sensory levels at six weeks and then recovered two levels by three months, one patient who had additional elective surgery for hardware repair, and one patient who showed deterioration three levels due to the presence of a syrinx.

    According to Fehlings, of 330 adverse events, 290 were felt to be unrelated to the drug, 40 were thought unlikely to be related, and 0 were deemed to be possibly, probably, or definitely related to the treatment.

    Preliminary analysis of the neurological outcomes in this study "appears promising," he explained. Patients with this type of injury do show some spontaneous recovery, Fehlings noted, "but the recovery rates are generally felt to be fairly low, perhaps on the order of about 5% to 10%. What we found in this study was about a third of the patients showed neurological improvement." At six months, 27% of patients showed improvement from ASIA A to B, C, or D.

    According to the results, Fehlings reported that by six months, seven patients had improved by two grades or more, with five at ASIA C and two at ASIA D.

    The rate of conversion from ASIA grade A to B, C, or D correlated with the dose administered at six weeks and three months, but the correlation was not seen by six months.

    "While we recognise that, given the lack of randomisation and a placebo control arm in our phase 1/2a trial, no conclusions can be made regarding efficacy, it is relevant to place the extent of neurological recovery seen in our patient cohort into context," explained Fehlings. For 2-grade or better improvement to ASIA C, D, or E, their rate of 19% at six months was 1.5 to 3-fold higher than seen in previous studies.

    "So at the end of the day, what we can say is that it's safe, it's feasible, and the results look promising," Fehlings concluded. "The next step will be to do a prospective randomised study, and the plans for that are now in the works. We hope to initiate that within the next few months."
    Last edited by GRAMMY; 1 May 2011, 12:08 PM.


      The Phase 1/2 Safety Trial has concluded. I believe they are now recruiting for a Phase 3 Randomized Study. (NCT01162915) The article below is from Sam Maddox (paid blogger from CDRF).


      Acute Drug Cethrin "Very Encouraging" in Trial

      Posted by Sam Maddox
      Friday, March 25, 2011
      Comments (16) | Add Comment
      This just in: data has been published in the Journal of Neurotrauma from an acute SCI Phase I/IIa (safety) trial for a drug called Cethrin. The primary author is Michael Fehlings, M.D., Ph.D., University of Toronto, a member of the Reeve Foundation’s Science Advisory Council, a key advisor to the NeuroRecovery Network a principal investigator in the Foundation's North American Clinical Trials Network (NACTN).

      In a nutshell, Cethrin appears to be safe and is well tolerated. Those with cervical injuries achieved significantly higher motor and sensory recovery than would be expected. Patients with thoracic injuries were not affected much by the drug.

      According to the authors, “a cervical ASIA Grade A-injured patient is likely to spontaneously improve by approximately 10 motor points during the first year after SCI, while we observed average improvements of 21.3 and 27.3 points, at 12 months.”

      The trial was not blinded nor did it feature a placebo control; nonetheless, say the authors, it is “very encouraging.”

      The authors concede that many SCI folks “show some recovery after the first few days in under intensive care, and it has been argued that an ASIA assessment at 24 hours is not as reliable as one taken at 72 hours when the patient is more stable.”

      But there appears to be more going on than spontaneity. “The continued improvement that we observed between week 6 and week 52 is also encouraging. If some recovery were due to regeneration of injured fibers, this would be expected to be a slow process, similar to what was observed.”

      Further, the authors note: “While much emphasis is typically placed on motor recovery, the fact that the cervical patients achieved substantial sensory recovery is also noteworthy, as such sensation may have a crucial protective function for skin areas that are sensitive to pressure sores, and the sensory feedback may help in seating balance.”

      Wondering why cervical injuries would respond more favorably? The authors of the paper expected this result, “based on the anatomy of the spinal cord, motor innervation patterns, and their relative contribution of these differences to ASIA scoring.” In other words, a change in cervical-level function has a much greater effect on the ASIA score. Put another way, a one-level improvement in the neck area has more impact on ASIA score than a one-level gain in the mid-back.

      Also, “thoracic injuries are often associated with significantly more trauma to surrounding tissues than are cervical injuries, creating an environment that is more likely to allow for systemic absorption of the locally-administered Cethrin …”

      How does it work? Cethrin is a recombinant (engineered) version of C3 transferase, which is derived from Clostridium botulinum; it is, therefore, a cousin of Botox. The drug blocks the common pathway, called Rho, by which myelin-related inhibitory proteins affect spinal cord nerve cells. If these various inhibitors (e.g. Nogo, proteoglycans) are activated by trauma, spinal cord axons are stopped dead in their tracks. Animal models have shown that blocking Rho spurs spinal cord axons to regenerate; Cethrin also has a protective effect on other nerve cells. Treated animals improved functional recovery.

      Five different doses of Cethrin were studied in the trial, from 0.3mg to 9mg. Forty-eight patients were enrolled in the trial, aged 16-70 years; 35 completed the trial – 23 with complete thoracic SCI, 12 with complete cervical SCI. Of those that did not complete the study, nine were lost to follow-up, two died (unrelated to treatment), one withdrew consent, and one refused to return to complete visit. There were no serious adverse events attributed to Cethrin, including pain.

      Motor score ASIA assessments were completed within 12 hours prior to surgery and between 48-72 hours following surgery, as well as at 3, 6 and 12 months later.
      Here’s what is meant by the ASIA score:
      A = Complete: No motor or sensory function is preserved in the sacral segments S4-S5.
      B = Incomplete: Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4-S5.
      C = Incomplete: Motor function is preserved below the neurological level, and more than half of key muscles below the neurological level have a muscle grade less than 3.
      D = Incomplete: Motor function is preserved below the neurological level, and at least half of key muscles below the neurological level have a muscle grade of 3 or more.
      E = Normal: Motor and sensory function are normal.

      From the paper: “While the patient numbers are small, the observed motor recovery in this open-label trial suggests that BA-210 [working name of Cethrin] may increase neurological recovery after complete spinal cord injury.”

      The next step will be to do a prospective randomized study; the Fehlings group hopes to get that going within the next few months.

      The Cethrin trial was funded by BioAxone Therapeutics and Alseres Pharmaceuticals, based on the basic science of Lisa McKerracher, University of Montreal.

      By Sam Maddox