Experimental treatments for spinal cord injury:
What you should know (Version 2)
A guide for people living with spinal cord injury, their family, friends and health care professionals John D Steevesa, James W Fawcettb, Mark H Tuszynskic, Daniel P Lammertsed, Armin Curte, Michael G Fehlingsf, James D Guestg, Naomi Kleitmanh, Andrew R Blighti, Douglas J Brownj, Michael Haakk, Harvinder S Chhabral, Hideyuki Okanom, Li Jianjun. a. ICORD, University of British Columbia & Vancouver Coastal Health, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada Cambridge University Centre for Brain Repair, Robinson Way, Cambridge, CB2 2PY, UK Center for Neural Repair, University of California at San Diego and VA Medical Center, La Jolla, CA Craig Hospital, 3425 South Clarkson Street, Englewood, CO 80113-2811, USA Spinal Cord Injury Center, Balgrist University Hospital, Forchstrasse 340, CH-8008 Zurich, University of Toronto, Krembil Neuroscience Center, Spine and Spinal Cord Injury Program, Toronto Western Hospital, 399 Bathurst St. Toronto Ontario M5T 2S8, Canada Department of Neurological Surgery and the Miami Project to Cure Paralysis, Lois Pope LIFE Center, 1095 NW 14th, Miami, FL, 33136, USA National Institute of Neurological Disorders and Stroke, NIH, 6001 Executive Blvd, Bethesda MD 20892- 9525, USA. Acorda Therapeutics, 15 Skyline Drive, Hawthorne, NY 10532, USA Spinal Research Institute, Austin Health, 145 Studley Rd, Heidelberg, Victoria, 3084, Australia Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital, 251 E. Huron, Chicago, IL, 60611, USA Indian Spinal Injuries Centre, Sector C, Vasant Kunj, New Delhi, 110070, India Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku Tokyo, 160-8582, Japan China Rehabilitation Research Center, School of Rehabilitation Medicine, Capital Medical University,10 North Road, Fengtai District, Beijing, 100077, P.R. China. This guide can be freely printed or downloaded to any website (in an unaltered state).
Unlocked versions are available for translation (contact Dr. John Steeves, see below). Disclaimer: This guide is based on published scientific papers and the professional opinions
of the authors as of 2012. The fundamental information is similar to version 1 (2006) of this
document. The recommendations are subject to change as new knowledge becomes available.
This document is intended to be an additional resource for you, and is not intended to substitute
for the advice and direction of your health care provider, or replace current clinical treatments.
Users of this guide should periodically review the material to ensure that the advice herein is
consistent with protocols of any experimental treatment being offered to improve functional
outcomes after spinal cord injury.
Address for correspondence:
Dr. John Steeves, ICORD at UBC and VCH, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada (Email: [email protected]) We are grateful for the support of the following organizations that have contributed to one or more versions of this booklet. • Spinal Cord Outcomes Partnership Endeavour (SCOPE, International), International Collaboration On Repair Discoveries (ICORD, Canada), Christopher and Dana Reeve Foundation (USA) • Craig H. Neilsen Foundation (USA), Institut pour la Recherche sur la Moëlle épinière et l'Encéphale (France) • International Spinal Research Trust (UK) • Fondation internationale pour la recherche en paraplégie (Switzerland) • Japan Spinal Cord Foundation • Miami Project to Cure Paralysis (USA) • Neil Sachse Foundation (Australia) • Paralyzed Veterans of America (USA) • Rick Hansen Foundation (Canada) • Wings for Life (Austria). Table of Contents
Acknowledgements Table of Contents How do I tell whether a treatment is part of a valid clinical trial program? Why are clinical trials necessary? What makes a good clinical trial? What if I have already participated in a previous clinical trial? How are clinical trials structured and governed? What is required for your participation in a clinical trial? What is informed consent? How long wil I be required to participate in the clinical trial? What are the various trial phases? What if you get assigned to the control group? What should you expect after a SCI clinical trial? Where can you get good advice? What treatments are available now? What about Rehabilitation Strategies and Assistive Devices? What are some of the current experimental treatments proposed for SCI? APPENDIX A: Previous Drug and Cell Transplant Clinical Trials Current Drug and Cell Transplant Clinical Trials APPENDIX B: What to ask before taking part in a clinical trial or human study? What should the answers be? APPENDIX C: Glossary of selected biomedical terms APPENDIX D: Selected websites (for further information) APPENDIX E: Selected references

Experimental Treatments
encouraged to discuss these issues with your health care team. for Spinal Cord Injury:
What you should know
(Version 2)
Sustaining a spinal cord injury (SCI) is extremely traumatic, both
physically and psychologically. You may
have already had surgery to stabilize the
spinal column and reduce the possibility
of further damage. You are How do I tell whether a treatment is
understandably distressed about the part of a valid clinical trial program?
functions you may have lost below the It can be difficult to tell the level of spinal injury. You wish to difference between a bona fide clinical recover any lost abilities as soon as trial and a treatment program that claims possible. You, your family or friends to be a trial. Perhaps the easiest way to may have searched the Internet for tell the difference is whether the treatments and cures. investigator or clinic is asking you to pay After a spinal cord injury, patients for the treatment. If you, your family or are often told that there are no validated friends are asked to pay for an drug or cell transplant treatments that experimental treatment, it is probably will repair the damage and restore not a clinical trial! You should be voluntary movement. Regardless of cautious about any experimental what you may hear or read, this is still treatment being offered for payment. true. This advice is given with the best This booklet offers advice to help you intentions, in the hope that people will make an informed decision about focus on their rehabilitation and participating in a trial, as well as to avoid recovery programs, rather than looking paying for unproven experimental for a miracle cure. Nevertheless, great treatments and placing yourself at risk. advances have been made in the There are 5 appendices (A-E) attached science of spinal cord repair and to this booklet. treatments that could one day improve In this booklet we also provide an the function of people living with SCI are update of past research approaches and being tested in animals. But there are where their progress stands at this time. also people who might offer you an Although validated restorative unproven treatment, claiming they can treatments of the spinal tissue have yet restore function if you have money to to be established, there are a number of clinical trials (as of 2012) currently This document was first created underway or about to commence in 2006 and has now been revised and (please see APPENDIX A of this
updated as of 2012. It is intended to address some of the questions you may have concerning various therapies or treatments after SCI. You are

You are curious, but hopefully people will achieve dramatic recovery. cautious, and wish to know how to best The rehabilitation treatments people evaluate the credibility of a new receive after SCI (e.g. strength training treatment or a clinical trial before exercises, therapies to improve mobility agreeing to participate. You want to and/or hand function) will provide know what questions to ask and what improvement in activities of daily living answers you should expect from and mobility. The rate of recovery is someone explaining a clinical trial or usually greatest over the first three offering an experimental treatment months, but with continued rehabilitation (please see attached questionnaire - effort, functional improvement can APPENDIX B at end of booklet). The
continue for a year or even more. differences between a rigorous clinical There is wide spread consensus trial and any "experimental treatment" that rehabilitation training maximizes being offered for payment can be greater independence for activities of daily living and improves mobility. Physical and occupational rehabilitation training is now widely available. Even the controversial "medical tourism" clinics, offering cell transplants to people, include vigorous rehabilitation. Thus, for people who have received an experimental drug or cell transplant, it can be difficult to tell whether recovery is due to some unrecognized spontaneous healing, the effects of Why are clinical trials necessary?
rehabilitation, or the effect of the It can be surprisingly difficult to experimental treatment. Effective clinical find out if a treatment or therapy is safe trials are designed to accurately and and if it really works. If a patient reliably determine which of these receives an experimental therapy and possibilities is the cause of any experiences some recovery, they observed recovery. commonly believe they got better as a The Placebo Effect. Everyone direct result of the new treatment. But has hopes and aspirations, including the improvement may not have been scientists, clinicians and patients. In caused by the treatment. There are two medicine, our desires can lead us to other possibilities to consider. expect or report outcomes that are not Rehabilitation Benefits and the result of a therapy. Thus, even after "Spontaneous" Recovery. Immediately after a spinal cord injury, some people containing no medication, a patient's are completely paralyzed below the area hope may influence their perception and of injury. However, spontaneously, or lead them to report an improvement. more often with active rehabilitation Likewise, the unintended biases of programs, most people will recover at scientists and clinical investigators can least a little function, while some recover lead them to conclude a therapy has more function and a small number of benefit when the improvement is due to some other influence. To truly understand whether therapists want the treatments they there is a causal relationship between a provide to improve an individual's therapeutic intervention and any independence, mobility and quality of subsequent improvement, we need to life. If human studies are not adequately compare outcomes of a group of controlled, the desire (unintended patients who received the treatment to biases) of people living with SCI or those in a control group who did not. While not always feasible, a placebo or investigators may lead them to conclude "sham" treatment given to a group of an improved function. This is why it is control subjects (without letting either best to "blind" both the trial participants the patients or the clinicians know who and the investigators as to which person is receiving the active treatment or the received what treatment (experimental placebo control) is the most effective or placebo control). Sometimes this way to accurately measure whether cannot always be accomplished, but the there are beneficial effects of the investigator charged with measuring any therapy. In fact, without some type of improved function (outcome) must be control group during the later stages "blinded" (kept from knowing) what (Phase 2 or 3) of a clinical trial program, treatment was administered to the trial the research study will not be able to participant being examined. provide valid evidence of the therapeutic Bias on the part of doctors effects - good or bad. In a trial, randomly ("investigators") who conduct clinical selected control patients will receive a trials can pose a significant risk for the sham or placebo treatment and they will misinterpretation of trial data or, even sometimes also report a considerable worse, can lead to short-cuts in the improvement in their condition. If the scientific process of a trial, resulting in improvement in the control subjects is harm to people. Sometimes this bias is just as large as that reported by subjects While clinical trial receiving the actual investigators may be reimbursed for it is only logical and their work in conducting the research, reasonable to conclude the they should not have a direct financial experimental treatment has little or no interest in the outcome of the trial (such therapeutic benefit. as owning stock or other equity share in If an experimental therapeutic has
the sponsoring company). not completed a properly designed
investigator could benefit financially clinical trial program, there is a real
from the outcomes of a human study,, danger that treatments that do not
there is the possible temptation to report work or therapies that might do harm
a positive benefit. Institutional Review could become standard medical care.
Boards (the independent panels that safeguard patient rights and must approve scientific clinical trials) have What makes a good clinical trial?
strict standards for investigator People with spinal injuries want disclosure of potential financial conflicts to recover as soon as possible. of interest. Patients should be made Scientists also want to see their aware of any potential conflicts of discoveries help people with spinal interest situation by the investigators as injuries. Physicians, surgeons and a part of the informed consent process.

If this is not disclosed, then it is within of the most difficult challenges medicine your rights to ask. has ever attempted. Yes, like winning the grand prize in a large lottery, there is A good (valid) clinical trial a very small chance that a treatment (human study) usually will test a offered without completing a clinical trial treatment only after it has undergone might work, but it is much more likely extensive investigation in animals, or in that it will be ineffective or even do some other related human disorder, and harm. We strongly advise you to only will have shown evidence of safety and participate in objective clinical trials a potential for a beneficial effect. A where there is compelling evidence of clinical trial program has several phases positive benefits from previous animal (see below). It will be carefully designed experiments or use of the treatment in a to compare a group of participants related clinical disorder. receiving the experimental treatment with others (controls) receiving no treatment (or sham procedure), a placebo substance or the current best standard of care. Without completing a clinical trial that compares the effects of a treatment in the experimental group to the outcomes from an appropriate control group, it is impossible to determine if the treatment is safe and provides a meaningful benefit. Treatments offered for material gain: Unfortunately, if patients are desperate, as they might be after SCI, What if I have already participated in
there is an opportunity for less a previous clinical trial?
scrupulous organizations to offer The following might not apply to unproven treatments to those who can most people currently living with SCI. pay. You should question any request Nevertheless, patients who have for payment of an "experimental" clinical already participated in a previous clinical trial procedure, as this is not allowed in trial, such as an experimental therapy valid clinical trial programs. Depending for SCI (sanctioned by regulatory on your health care coverage, you, your authorities or not), may or may not be health care or government insurance eligible to participate in a subsequent plan may be expected to pay for the trial. The reason for this is that a current standard of medical care you previous therapy may have altered the receive during your participation in a spinal cord in subtle unknown ways, clinical trial. You should ask and discuss making it difficult to know whether the what, if any, payment is required for current treatment has a benefit. You your participation in a trial, but the must discuss with the investigators of treatment itself and all the following the current trial, any of your past assessments should be free. experiences with experimental Creating new treatments for Nevertheless, should a those with spinal or brain injuries is one treatment be subsequently approved as a treatment for SCI, you may be able to placebo control, while the other group receive that treatment, providing you receives the placebo control first, meet the eligibility requirements (for followed by the experimental treatment. example, the treatment benefits a Regardless, the examiners assessing person who has lived for some time with the outcomes in such trials are "blinded" as to what was done and at what time. Another exception relates to early How are clinical trials structured and
Phase 1 clinical trials (see below), which governed?
primarily focus on testing the safety and the feasibility for offering the treatment. The key component of most These early studies are usually clinical trials is the random assignment accomplished with a small number of of participants to either an experimental and are generally treatment group or control group. As completed without a control group. mentioned above, the control group Nevertheless, a control group will be helps eliminate the possibility that many part of any subsequent Phase 2 or other factors, which cannot be controlled Phase 3 trials that test whether the by the design of the study, could treatment is effective. influence the trial outcomes. Random As mentioned above, it is also assignment helps ensure that these important to eliminate bias by trial other factors influence the groups investigators or study subjects. This is equally. For example, most people why trial programs that successfully receive active rehabilitation after SCI. pass Phase 1 safety evaluation always By itself, rehabilitation can improve have a later trials to examine efficacy function in people living with SCI, which where the investigators are "blinded" to is why we recommend you participate in which group a subject belongs available rehabilitation opportunities. (experimental or control). Whenever Thus without a control group that will possible, neither the subjects receiving receive a similar amount of active the experimental treatment or the rehabilitation, the investigators would placebo, nor the doctors or therapists not know whether any observed assessing the subjects know who improvement was specifically due to the received what treatment. Such a experimental treatment being tested. "blinded" protocol preserves the An exception to the use of a objectivity that is necessary to separate control group may be made in accurately determine whether a a trial where patients have established a treatment is safe and beneficial. very stable level of function (this would Finally, valid clinical trials should normally be people who have lived with be registered with the appropriate SCI for at least 6-12 months). In this national regulatory authority (such as event, the participants may act as their the Food and Drug Administration, FDA, own control and their capabilities will be in the United States or the European measured before and after a treatment Medicines Agency, EMA). Bona fide to see if there is an improvement. trials will have approval from the local Sometimes two groups are used with human research ethics committee (such one group receiving the experimental as an Institutional Review Board or treatment followed by a period with the

IRB). An increasingly common timeframe. The location and severity of occurrence is the registration of the trial your spinal cord injury may or may not on a central website. meet the eligibility requirements, or you may have other conditions that would limit your suitability for participation or for proper evaluation. When an experimental treatment is being examined in a clinical trial, it is usually important that all the participants be fairly similar to each other (in terms of their symptoms). Too much variability between subjects can confuse and alter the accurate determination of the trial results. Like many neurological disorders, SCI can result in varying The ClinicalTrials.Gov website can degrees of impairments and you have serve as a source of valuable probably already noted that you have information for patients, clinicians and been initially classified along a scale scientists. The physician investigator extending from complete sensory and asking you whether you wish to motor loss to very minimal sensory or participate in a clinical trial will provide motor loss. If we were to put all the you documented evidence that all different types of SCI subjects into one national and local regulatory and ethical group, it is likely that the different human study approvals have been degrees of spontaneous recovery would make it difficult to determine whether the experimental therapy was beneficial. This is why clinical trial programs are What is required for your
often repeated for each sub-type of a participation in a clinical trial?
disorder or disease. Before anyone can be enrolled in a trial they are usually screened against What is informed consent?
a set of pre-determined criteria to see if they qualify to participate in the proposed Should you meet the eligibility clinical study. Not all patients will qualify requirements to participate in a clinical to participate in a given trial. Every trial trial, you must also give informed should have specific conditions (inclusion consent. This involves a discussion with / exclusion criteria) that must be satisfied a trial investigator about the specific trial for an individual to participate. Most experimental treatments have a history 1. You should have the nature of the of being better for certain conditions and experimental therapy explained to situations. For example, the past you in detail, including prior evidence may indicate a drug or cell evidence in animal studies or other transplant should be administered within clinical disorders; a specific time window after SCI and your 2. You should be told about the now be outside that potential benefits and risks of participating in the trial;

3. You should be told that you may be randomly assigned to either the experimental treatment group or the placebo control group (or why the trial at this phase does not include a control group); 4. You should be informed of all study procedures, the duration of your participation, and what is required of you for follow-up visits; 5. You should understand how the cost of any standard clinical care or rehabilitation training, How long will I be required to
accompanying or associated with participate in the clinical trial?
the trial (including travel costs), will After the informed consent process is complete and you have 6. You should be told if you will formally volunteered (enrolled) as a receive compensation to participate participant, you are likely to be randomly assigned to either the experimental 7. You should be told how treatment treatment group or control group. You or compensation for possible may or may not know whether you will research-related injury will be receive the experimental treatment or the arranged and who will pay for it; control treatment; remember, "blinding" is 8. You should be informed of the important to objective results. You will alternatives to participation in the then undergo an initial baseline assessment to confirm your status and 9. You should be informed of your your capabilities at the right to withdraw from participation beginning of the trial. During the trial, in the study at any time for any there will be some follow up reason; you should also be assessments where it will be necessary informed that the investigators may to attend the clinic. Clinical trials may last remove you from the study and the for different periods of time, depending possible reasons; on the type of treatment involved, but 10. You should have adequate time to follow-up examinations may be required ask questions and be fully satisfied at intervals for several months or even a that your questions have been few years. These details should be explained to you at the time you are explained informed consent. One way to judge the quality of a clinical In some trials you will be asked to trial is the thoroughness of the informed donate several hours so that thorough consent and the care that is taken to fully assessments can be performed. Most of inform you about all significant risks. This these examinations involve little or no is especially important when the long- discomfort and may include a physical term effects of a treatment are not well exam, routine blood tests, and assessment for the capacity to perform activities of daily living. Imaging studies

such as MRI may be obtained and tests functional activity assessments are also of spinal cord conduction may require included as part of the Phase 1 study, electrodes to be placed on your skin so but conclusions will not be made about electrical activity can be measured the benefit of the treatment. It should be across the injury. These evaluations are noted that safety is always monitored used to examine what changes, if any, throughout all clinical trial phases. have occurred in spinal cord function. Phase 2 is a second round of
You should not have to pay for these studies designed to assess whether the visits, but travel and accommodation treatment stimulates any expenses should be paid. biological activity within the target tissue It usually takes a progression or provides a clinically meaningful through three separate clinical trial benefit for the intended body functions. before an experimental The outcomes from the experimental treatment will be approved by a group are compared to the control group government regulatory agency for use in receiving an appropriate placebo humans with that specific disorder. Each treatment or standard of care. Because trial phase is more demanding than the Phase 2 trials often involve as many as previous phase in terms of how it is 200 experimental and control subjects, conducted. You would likely only be they frequently include multiple study involved in one trial phase, and you centers. Phase 2 trials are commonly should be told where the testing stands used to determine the best dose and and in which phase of the trial program timing of treatment, as well as the best you are participating. outcome tools to measure any positive (or negative) effects of a treatment. This development phase is important to What are the various trial phases?
establishing the best protocol for the Phase 1 is to find out if the
pivotal Phase 3 study. Even if the treatment is safe and possible to evidence from Phase 2 studies suggests adequately test in human subjects. A a possible benefit, this still does not fairly small number of participants, usually prove that the treatment will be usually less than 50, are given the reliably effective as the number of treatment (often at slightly different participants is still relatively small. doses) to see if there are any Generally, the therapeutic unexpected, harmful side effects. This is complete the most important (pivotal) the one clinical trial phase where there stage - Phase 3. might not be any control subjects, as the emphasis is on safety and tolerability of the experimental treatment. Phase 1 trials are sometimes referred to as "open label" trials as everyone (participants and investigators) knows the treatment and there are no "blinded" assessments. A series of routine clinical tests are undertaken and the participant is asked to report any discomfort or change in body function. Sometimes, Phase 3 is the pivotal trial phase
being in the control group may be an to more fully test the effectiveness and safety of the therapy and involves the Volunteers participating in a trial, largest number of participants at whether they are in the experimental or multiple locations (often in several control group, should always receive the countries). This phase helps the current best care available. The trial investigators learn if the treatment works investigators will have a policy on what well enough to improve outcomes in a to offer members of the control group at more varied population, typically men the end of the trial, which may include and women, different ages, races, etc. the trial treatment if it is effective and Furthermore, it helps ensure that you still meet the eligibility criteria. If this different centers can provide the is not clear, you need to ask. treatment in the same manner and equally well. If the treatment demonstrates a clear benefit with no What should you expect after a SCI
serious side effects (adverse events) clinical trial?
then it is eligible for consideration for approval by a national regulatory As of 2012, there are no approved agency as a treatment for the disorder cures for SCI. As you are already aware, being studied in the trial. the brain and spinal cord are the most complex tissues of the body and the most challenging to repair. We do know that What if you get assigned to the
some surgical procedures reduce the control group?
chance of further injury and active rehabilitation training programs can Most patients would obviously improve recovery or adaptive skills, prefer to receive a beneficial treatment. especially when there is some preserved However, when studying an function below the level of spinal cord experimental treatment in a clinical trial damage. If a new treatment is determined program, we do not know whether it has to provide some functional benefit after any benefits or significant risks. As we completing a clinical trial program, it is still described above, it is impossible to unlikely that it will provide a complete learn if a treatment really works and is reasonably safe unless there are appropriate control patients with whom Progress is incremental and it is to make comparisons. If we already most likely that a combination of were certain that available evidence treatments will provide better outcomes in proved a treatment is effective, it would the future. For example, cancer therapy be unnecessary and unethical to delay often involves a combination of treatment by further testing. treatments, including surgery, drugs and definition, for a trial to be valid, clinical radiation therapy. It took decades for investigators adopt a "wait and see" scientists to determine the best perspective about the risks and benefits, combinations for current cancer therapy until all trial phases are completed. If by With continued study, mischance the treatment has an scientists and clinicians will also refine the undesirable or harmful side effect, then most appropriate combinations for SCI.

Where can you get good advice?
anatomical and neurological evidence that the spinal cord has been Reliable information is always the compressed and/or the vertebral goal. You have a number of avenues column is damaged and unstable. you can explore. Whatever you choose Many factors impact the timing of any to follow, you should confirm all surgery including transport to a hospital information from more than one source. capable of performing the necessary Some of your options are: Worldwide, there is a • You can discuss your options with developing practice for early surgical your physician(s) decompression of the compressed or contused (bruised) spinal cord You can visit several websites, (preferably within 24 hours of injury). which provide a variety of Many surgeons agree that fractures of information. There are a number of the vertebral spinal column should be professional societies, non- stabilized, which may involve the governmental spinal cord insertion of rods and screws to properly foundations, government agencies, align the vertebral column or fuse and university or hospital-based adjacent vertebrae to strengthen the research centers where you can vertebra, promote bone re-growth, and seek advice. Many of them are reduce the likelihood of further spinal staffed by people who themselves cord injury in the future. During this have spinal cord injuries. procedure all abnormal pressure on the • You can study the available spinal cord and spinal nerves from published scientific and clinical should be reduced, maximizing the literature. This may seem obvious, potential for recovery. For more details, but it can also be intimidating if you on these and other treatments, please don't have a biomedical research Nevertheless, the most important question you ever learned in life was the question - WHY? • Keep reading and keep asking
questions. An earlier version of
this handout had a more extensive
discussion of the above topics
(some might say too detailed a
description). However it is still
available at the ICORD website

What treatments are available now?
Patients with SCI should undergo appropriate surgical procedures when they are medically fit to withstand the surgery and where there is clear sufficient to maximize functional What about Rehabilitation Strategies
outcomes after SCI. and Assistive Devices?
However, the consensus is any active rehabilitation is better than no Many spinal cord injuries are Once again, if an incomplete and sometimes slightly individual is medically stable and will not asymmetrical, which means there is suffer any detrimental effects due to the some residual function below the level movements associated with rehabilitation of spinal damage and it may not be activities, then rehabilitation training can equal on both sides of the body. This be started within weeks after SCI. There spared capability is often noted by are an extensive number of activity retention of some sensory feeling (e.g. dependent rehabilitation studies and detection of a pin prick) or ability to trials underway. We cannot begin to move part of a limb (raise a shoulder, cover these rehabilitation strategies. For move a finger, or wiggle a toe). In an a detailed discussion of the strength and effort to maximize functional recovery limitation of the many rehabilitation after SCI, a variety of active rehabilitation strategies have been ( Do not hesitate developed to build upon and extend to discuss active rehabilitation strategies residual functions, including repetitive with your therapist and/or physician. voluntary movement training, strength training, and constraint use therapy (e.g. where the better functioning arm is constrained to force the use of the weaker limb). Some muscle movements, such as hand function or diaphragm contractions (to power breathing) have been enhanced by functional electrical stimulation (FES) of specific nerves or muscles. Thus, there is an emerging consensus that active rehabilitation after SCI is important and effective in preserving body functions, as well as improving the recovery of functional activity after SCI. By active rehabilitation, we mean activities that involve the individual contributing their voluntary efforts to the performance of the task. Passive rehabilitation therapy Active rehabilitation (physical, might include massage and the occupational, or psychosocial) is likely to movement of an individual's limbs magnify the benefits from any other through the entire range of motion therapeutic intervention for improving normal for that limb. Passive outcomes after SCI, including any drug rehabilitation is likely to be a part of any or cell transplant. In addition, active treatment protocol, but is unlikely to be rehabilitation maintains bone and muscle integrity, fitness, and reduces ongoing experimental treatments for SCI? The medical complications after SCI. For a accompanying table (APPENDIX A) lists
detailed discussion of published some of the treatments that have been evidence of SCI rehab strategies and investigated and are currently being practices, please consult the SCIRE investigated in notable clinical trials. (Spinal Cord Injury Rehabilitation Potential therapeutic interventions (new Evidence) report, which is available as a drugs, cell transplants, rehabilitation free download ( strategies or assistive devices) are directed to one or more of several target A number of currently available drug treatments can reduce spasticity and pain, or improve metabolic functions, • Neuroprotection as well as provide better management of amount of tissue damage and bladder, bowel, respiration rescuing injured nerve cells cardiovascular activity. There are also (neurons) to keep them from dying programs to help people living with SCI in the hours or possibly days have children. Engineers have following the injury developed a number of assistive devices • Repair / Regeneration - reducing to provide improved motor function and long-term pathology of the injured increase mobility within the community. cord, promoting new outgrowth and Although these issues are of equal or connections from spinal neurons, greater importance to the quality of life possibly replacing lost cells to for people living with SCI, it is beyond the rebuild the damaged spinal cord scope of this article to cover the ongoing care and treatment of all medical • Neuroplasticity - facilitating the challenges and community participation formation of new functional after SCI. Your health care professionals connections between surviving can advise and guide you. cells and/or replacement cells, thereby enabling recovery of function through the creation of new circuits • Replace / Assist function - incorporation of an assistive (engineered) device to improve independent activity and/or mobility Researchers around the world are working hard to develop new treatments to achieve the above aims. Some treatments are showing promise in animal experiments; a few are already in What are some of the current
early stage clinical trials experimental treatments proposed
APPENDIX A below).
With all that has been discussed so far, what is the current state of APPENDIX A: Previous Drug and Cell Transplant
Clinical Trials and Studies
Timing of Treatment &
Results Summary
Status of Clinical Trial
Methylprednisolone Anti-inflammatory Acute SCI (< 8 hrs); Missed statistical significance on sodium succinate completed several Phase primary outcome (but still used in some centers). Undergoing combination trials (see below) Acute SCI; completed Missed statistical significance on primary outcome (abandoned) and neural repair Acute SCI; completed No significant benefit (abandoned) releasing hormone Acute SCI; completed No significant benefit (abandoned) and neural repair transplantation (Procord) Fampridine Chronic SCI; completed Missed statistical significance on sensitive potassium primary outcome (but subsequently Ampyra, Fampyra) channels, prolongs approved to improve walking in people action potential living with multiple sclerosis) Acute SCI; completed Missed statistical significance channel antagonist) intracellular cell Acute SCI; completed Open-label (unblinded) results signaling for axonal suggest possible benefit, but Phase 2 randomized control trial required Anti-inflammatory Acute SCI completed Statistical significance achieved on (commonly used for Phase 2 trial with some some measures, but funding needed statistical significance for Phase 3 trial program Acute SCI; completed Phase 1 trial completed, but no results and neural repair published to date Anti- inflammatory No trial results reported to date, Trial ongoing (but not (conflicting results reported in number of red blood preclinical studies) when administered with MPSS ATI-355 (anti- Acute SCI; completed No trial results reported to date, and neural repair Chronic SCI, several Several small studies report conflicting and neural repair open-label studies results about whether there are (source of olfactory completed and one benefits after SCI. ensheathing cells) blinded Phase 1 study (Australia) Mesenchymal stem Acute-Chronic SCI, Several small studies report conflicting cell transplants and neural repair studies ongoing (not results about whether there are benefits after SCI. Interventional clinical trials are routinely registered onbased on legal requirements* and because scientific journals may require registration for publication of trial results. Investigators may choose not to register some early phase trials and those testing behavioral interventions are sometimes not registered, even though they may be important and scientifically rigorous studies.
APPENDIX A: Current Drug and Cell Transplant Clinical Trials
Sponsor /
cells into spinal cord; intense rehabilitation cervical canal stenosis Current Clinical Trials (continued)
Sponsor /
NCT01446640 General functional assessment escalating trial olone; ± oral lithium Current Clinical Trials (continued)
Sponsor /
Not receiving PT incomplete tetraplegia The above table is abstracted from the clinical trial registration website.
using the search term "Spinal Cord Injury" and is updated
quarterly (see Please refer to attached APPENDIX C: Glossary.
The table includes those trials from the search that: 1) are currently or soon-to-be recruiting subjects; 2) are interventional (tested an intervention/treatment) using drugs, cell therapies, surgery, or hypoxia; and 3) targeted neurological or related functional improvement as outcome measures. Interventional clinical trials are routinely registered on based on legal requirements* and because scientific journals may require registration
for publication of trial results. Investigators may choose not to register some early phase
trials and those testing behavioral interventions are sometimes not registered, even
though they may be important and scientifically rigorous studies.
*U.S. Public Law 110-85 requires the registration and reporting of results of "certain applicable
clinical trials," i.e. controlled interventional clinical trials that are subject to FDA regulation and
that involve a Drug or Biologic (other than Phase I investigations), or Device (other than small
feasibility studie
NCT number:
trials registered withare assigned a registration
number that begins with NCT (e.g. NCT012345678). The number listed in the above table can be used in the search field to access the specific webpage describing the trial, the study centers, and contact information. IV: intravenous—administration of a drug by vein
IT: intrathecal—administration into spinal fluid overlying dorsal surface of spinal cord
subcutaneous—administration of a drug by injection beneath the skin
Phase 1/2: phases 1and 2 are combined with blinded assessment of clinical outcomes.

APPENDIX B: What to ask before taking part in a clinical trial
or human study?
(your participation checklist)
Note: most of these questions should be answered during the informed consent process Question
Additional Information
1. Safety
a. Are there safety risks associated with this experimental treatment? b. Could my condition or my health get worse after this experimental treatment? c. If so, can you describe the possible risks associated with this experimental treatment? 2. Possible benefits
a. Can you describe the possible specific benefits of this experimental treatment? b. Can you describe the maximum level of recovery I might see after this treatment? c. Can you describe how any potential benefit will be measured? 3. Clinical trial protocol
a. Is this study registered as a clinical trial with an appropriate qualified regulatory body? b. Can you describe what clinical trial phase this particular human study falls within (Phase 1, 2, or 3) and what is the emphasis of study for this phase of the trial program? c. Is there a control group in this study? d. Could I be randomly assigned to the control e. Can you tell me how long I wil be assessed for any change in outcome? f. Wil I be blinded to whether I have received the experimental or control treatment? g. Will the investigators and examiners be blind to what treatment I have received? Question
Additional Information
4. Payments and costs
a. Do I have to pay for this treatment? b. As a possible participant, are there other costs I have to pay to be involved in this study? c. Will my expenses associated with participating in this study be paid (e.g. travel to center for fol ow-up assessment)? 5. Participation in Other Trials
a. Will my participation in this clinical trial limit my participation in other SCI clinical trials? b. If I am assigned to the control group and the experimental treatment is subsequently shown to be an effective therapy for my type of SCI by this clinical trial program, will I be eligible to receive this treatment later? 6. Preclinical or prior clinical evidence
a. Can you describe the preclinical or prior clinical evidence that indicates this experimental treatment might be beneficial? b. Have these findings been independently confirmed by other researchers? c. Are there any dissenting opinions and do these arguments have some validity for not going forward with this treatment? 7. Independent assessment of the
treatment and investigator
a. Can you provide me several names of
scientists and clinicians (not involved with this study) who can provide me independent advice about this treatment and your APPENDIX B (continued): What should the answers be?

So what do we, the authors, say should be the general answers to these questions?
Please see below, but regardless of our opinion, it is a personal decision for which the
individual living with SCI has to weigh the possible benefits against the possible risks in
determining their course of action.
1. Safety
Are there safety risks associated with this experimental treatment? Answer: should be YES; no one can guarantee total safety, but some information should be available about possible risks from either pre-clinical data or earlier Phase clinical studies. Could my condition or my health get worse after this experimental treatment? Answer: should be YES again; if someone states there are little or no risks you should be wary. However, small the chances, there is always the possibility of some problem. If so, can you describe the possible risks associated with this experimental treatment? Answer: the investigator should be able to discuss in detail the possible risks associated with this human study (clinical trial).
2. Possible benefits
Can you describe the possible specific benefits of this experimental treatment? Answer: the investigator should describe a range of possible benefits ranging from very subtle to modest functional improvements. Can you describe the maximum level of recovery I might see after this treatment? Answer: anyone who claims you are going to make a dramatic recovery with the return of almost full function should be avoided, as there is no evidence for any treatment having such striking outcomes, even in preclinical animal studies. c. Can you describe how any potential benefit will be measured? Answer: the investigator should be able to describe a number of different measures that will be used to evaluate your progress after treatment.
3. Clinical trial protocol
a. Is this human study registered as a clinical trial with an appropriate, qualified regulatory body? Answer: should be YES and the investigator should be able to provide you the details immediately. If the answer is vague on this point, you should be concerned (approach with caution). b. Can you describe what clinical trial phase this particular human study falls within (Phase 1, 2, or 3) and what is the emphasis of study for this phase of the trial program? Answer: should be immediate and in as much detail as you want. c. Is there a control group in this study? Answer: should be YES. If not, then this should be a Phase 1 "open label" study (safety only). If not, then this human study is unlikely to be a clinical trial and you should be wary or avoid. However, if this is a study involving people who have lived with a spinal cord injury for many months or years, you serve as your own control. Once again the investigators should be able to provide details immediately. d. Could I be randomly assigned to the control group? Answer: should be YES for Phase 2 and 3 trials, If not, then this is likely not a valid clinical trial. e. Can you tell me how long I will be assessed for any change in outcome? Answer: This may be relatively short (days or weeks) or it could extend for as much as a year or more if the treatment is likely to change the course of your recovery over a prolonged period of time. Depending on the therapeutic intervention, it is possible that you may have to commit more time over the first few weeks and this may include hospital stay as an in-patient. Subsequently, you may be asked to return for assessments at defined times over the following months. Once you agree to participate, you should be willing to complete the full trial protocol, even if you feel you are not benefiting. Participants who withdraw from a study undermine the completion of the trial in a timely fashion and make it difficult to accurately interpret whether the treatment had any benefit. f. Will I be blinded to whether I have received the experimental or control treatment? Answer: If at all physically possible, the answer should be YES. If not, it should be a Phase 1 trial. If not a Phase 1 trial, then you should be wary that this is not a valid clinical trial. Sometimes you cannot help but know what group you are in, but the investigators should ask you not to tell the examiners whether you are in the experimental or control group until the trial is over and the data is analyzed. g. Will the investigators and examiners be blind to what treatment I have received? Answer: this should be a definite YES, unless it is a Phase 1 trial. If not, it is not a valid clinical trial to examine the effectiveness of a treatment and you should be suspicious. 4. Payments and costs a. Do I have to pay for this treatment? Answer: this should be NO. If Yes, then this is not a valid clinical trial. You should be suspicious and probably should avoid the offered treatment. b. Are there any other costs associated with my participation in this study? Answer: you should not have to pay for any procedure specifically related to a clinical trial program, but you, or your health care insurance provider, may have to pay for the current standard of medical care. c. Will my expenses associated with participating in this study be paid (e.g. travel to center for follow-up assessment)? Answer: should be YES. 5. Participation in other trials a. Will my participation in this clinical trial limit my participation in other SCI clinical trials? Answer: could be a possibility. The investigator should be able to outline which type of trials you may be excluded from in the future. For example, it is unlikely that participation in an acute treatment trial would later affect your potential participation to take part in a study at a later (chronic) time point. Nevertheless, the number of inclusion and exclusion criteria for any two trials is difficult to predict unless the protocols are known and compared. b. If I am assigned to the control group and the experimental treatment is subsequently validated as an effective therapy for my type of SCI by this clinical trial program, will I be eligible to receive this treatment later? Answer: could be a possibility, unless your SCI condition changed, or there was a limited time for treatment after SCI, which has now been exceeded in your case. Generally, once an experimental treatment has been approved by a regulatory agency for clinical use, you would be eligible for treatment. 6. Preclinical or prior clinical evidence a. Can you describe the preclinical or prior clinical evidence that demonstrates this experimental treatment is beneficial? Answer: the investigator should be able to outline the previous evidence, including the strengths and limitations of the treatment approach as defined by the preclinical (animal) or studies involving a related human disorder. b. Have these findings been independently replicated? Answer: this could go either way, but there should be some evidence that other researchers have obtained similar results when investigating this therapeutic target or treatments approach. c. Are there any dissenting opinions and do these arguments have some validity for not going forward with this treatment? Answer: the answer here is likely to be a qualified yes, as there are almost always some dissenting opinions about any proposed human treatment. Scientists are usually very critical of each other! The investigator should be able to provide you with a summary of the pros and cons for the treatment, but be wary of any treatment that is claimed to have no limitations. You , your friends and family will undoubtedly use the internet to look up information. We have provided you with a list of some of the reputable websites (Appendix D). If you run into biological or medical terms that you don't understand, we have tried to help by providing a glossary of some of the relevant terms (Appendix C). In any case, you should discuss your concerns and aspirations with your health care providers. 7. Independent assessment of the treatment and investigator a. Can you provide me several names of scientists and clinicians (not involved with this study) who can provide me independent advice about this treatment and your reputation? Answer: should be YES and you should be able to verify the credibility of the study and the credentials of the investigators via the internet.
APPENDIX C: Glossary of selected biomedical terms

NOTE: These terms are commonly used in the discussion of spinal cord injury
(SCI) and/or experimental treatments after SCI. They are provided for your reference, but we could not include every medical or biological term you might encounter.
Action Potential: a short-lasting ( one thousandth of a second) event where the cell membrane potential
(electrical difference across the cell wall) rapidly rises and falls. Action potentials occur in excitable cells, which include neurons, muscle cells, and some endocrine cells. Neuronal action potentials are conducted along an axon and are used to signal activation of that neuron. Action potentials are important for rapid cell-to-cell communication between neurons, especially over long distances, such as between the brain and spinal cord. Over long, large-diameter myelinated axons, action potentials can be conducted as fast as 425 kph or 265 mph (faster than most racing cars). Given the short distances involved in a reflex withdrawal (at most a few feet) it is understandable why it occurs so fast. In muscle cells (fibers) an action potential is the first event leading to contraction of the muscle fiber. Action potentials are also called "nerve impulses"." Activities of Daily Living (ADL): activities involved in self-care, sphincter management and mobility,
such as bathing, dressing, eating, and other skills necessary for independent living. Ambulation: walking, with or without the use of assistive devices such as a walker or crutches.
Apoptosis: see Neuroprotection
ASIA (American Spinal Injury Association):
a North American based society of physicians, surgeons,
scientists and other allied health professionals who treat or investigate SCI. For more information, see ASIA's website: ASIA Assessment: see below, International Standards for Neurological Classification of Spinal cord
Injury (ISNCSCI). ASIA Impairment Scale (AIS): (sometimes referred to as ASIA Grades) describes the completeness or
severity of a spinal injury. A booklet and training manual is published and made available by ASIA (see above) AIS A: no motor or sensory function below the neurological level of injury and all the way down to the end of the spinal cord (at the level of S4-S5 sacral segments). Also known as ASIA A AIS B: some sensory function below the neurological level of injury, including S4-5, but no motor function. Also known as ASIA B AIS C: some motor function below the neurological level, but half or more of the key muscles involved have a muscle strength score of less than 3, which is classified as non-functional. Also known as ASIA C AIS D: motor function below the neurological level, but half or more of the key muscles have a muscle grade of 3 or more, which is classified as functional. Also known as ASIA D AIS E: normal motor and sensory function. Also known as ASIA E Assistive, Adaptive, Supportive Devices: a variety of implements or equipment used to aid individuals
in performing tasks or movements. Astrocytes: see Glia.
Autonomic dysreflexia: An autonomic reflex causing a sudden, severe, increase in blood pressure in
response to noxious (painful) or innocuous stimuli, originating below the level of spinal injury. Autonomic dysreflexia is defined by an increase in systolic blood pressure greater than 20 mm above baseline systolic blood pressure. Symptoms can include headache, flushing (blushing), a stuffy nose, sweating above the level of the spinal injury, vasoconstriction (below the level of injury) and irregular beating of the heart. Autonomic dysreflexia can be triggered by an over-full bladder or bowel and is an ongoing medical complication, which occurs most often with an injury at or above the 6th thoracic level of the spinal cord and usually no earlier than 4-6 months after injury. Tetraplegics are more prone to this complication as their autonomic nervous system is unable to oppose the reflex. Balance: the ability of an individual to maintain the body in equilibrium with gravity both statically (e.g.
while stationary) and dynamically (e.g. while moving). Belmont Report: a report created by the former United States Department of Health, Education, and
Welfare (renamed the Department of Health and Human Services) entitled "Ethical Principles and Guidelines for the Protection of Human Subjects of Research." The text is available at: (also see Helsinki Declaration). Properly conducted clinical trials will adhere to the principles and guidelines of the Belmont report. Bias: the tendency of any factors associated with the design, conduct, analysis and interpretation of the
results of a clinical trial to make the estimate of a treatment effect (therapeutic benefit) that differs from its true value (usually assumed to involve an overestimation of benefit and/or an underestimation of risk). Blinded assessments: those evaluations conducted on a clinical trial subject where the evaluator does
not know or ask whether the subject is part of the experimental or control group. Blinded assessments are considered important to reduce any bias in the analysis of the effects of an experimental treatment. There are different levels of blinding: Single-blind studies: either the clinical investigator or the subject, but not both, are blinded. Double blind studies: neither the participating trial subject nor the investigators, institutional staff or sponsoring company are aware of the treatment each subject has received during the trial. Ideal blinding procedures would ensure that the treatments cannot be distinguished by subjective experience, appearance, timing, or delivery method by any of the subjects, investigators, research staff, or clinical staff. Information regarding which treatment was assigned to each individual will typically be held securely by responsible independent members of the study center (or the central data center). It wil not be matched with the data (trial outcomes) until after the study is completed, other than for the purposes of safety monitoring by an independent safety board. also see: Open Label Burst Fracture: is a shattering of the vertebra within the spinal column, usually the ventral round body of
the vertebra (side of the column pointing towards the stomach). The bone shards may compress the spinal cord and there my be a risk of a fragment piercing the spinal cord. Surgeons will often undertake an operation to remove bone fragments and stabilize the spinal column with various rods and screws. The surgery is similar to the procedures performed to fuse (join) to vertebral segments together when a herniated disk is removed. Cauda Equina Syndrome: a progressive neurologic syndrome characterized by lumbar pain, fecal and
urinary incontinence, and possible progressive neurological deficits caused by soft and hard tissue proliferation at the lumbosacral level of the cord, often associated with lumbosacral vertebral or disc damage (also see: Conus Medullaris) Central Nervous System (CNS): The brain and spinal cord. Information coming to the CNS or leaving
the CNS is conducted along nerves of the Peripheral Nervous System (or PNS). also see information under Neuron, Glia, Action Potential, Synapse. Clinical Endpoint: a specified or targeted outcome of a clinical trial, which is based on an evaluation of
the feeling, function or survival of a patient (subject). The results of a clinical trial generally evaluate the statistical significance (and hopefully clinically meaning) of differences between the number of people in the experimental treatment group who reached the pre-determined clinical endpoint as compared to the number of people who achieved the same clinical endpoint from the (placebo) control group. The endpoint may involve a measurement, a change in measurement, or the achievement of at least a certain level of change, pre-identified as a meaningful "response" for the treatment. Clinical Trial: a human research program usually involving both experimental and control subjects to
examine the effectiveness and/or safety of a therapeutic intervention. Prior to issuing a license for a new treatment of a disorder, a typical clinical trial program contains studies at three different stages or phases: Phase 1 is to find out if the treatment is safe and subjects are given the treatment (often at slightly different doses) to see if there are any unexpected, harmful side effects. Phase 2 is the second preliminary study designed to assess whether the treatment stimulates any positive biological activity within the target tissue or is likely to provide a clinically meaningful benefit for the intended body functions in the proposed subject population. Phase 3 is the pivotal trial phase to test the effectiveness and safety of the therapy and involves the largest number of participants at multiple locations. If the treatment demonstrates a clear benefit with no serious side effects (adverse events), then it is eligible to be considered for approval by a national regulatory agency as a clinical treatment for the disorder being studied. Complete and Incomplete SCI: terms used to describe the overal severity of SCI. Technically, SCI is
classified as complete if there is no motor or sensory function preservation in the sacral (most caudal) spinal segments. Thus, incomplete SCI is when there is some preserved motor or sensory function at the lowest sacral spinal level (S4/5). There can be extensive variability in the degree of preserved function after incomplete SCI. Conus Medullaris: is the terminal end of the spinal cord. It occurs near the first lumbar vertebrae (L1).
After the spinal cord terminates, the lumbar and sacral spinal nerves continue as a "freely moving" bundle of nerves within the vertebral canal and are called the cauda equina (literally, horse tail). Control: the comparison group in a clinical trial, which does not receive the experimental treatment being
investigated. The control group may receive a placebo (inactive substance), another treatment, or no treatment other than the current available standard of care and treatment for SCI. The outcomes of the experimental treatment group are compared to the outcomes of the control group. The use of a control group enables researchers to determine whether the new experimental treatment provides a statistically significant and clinically meaningful (functional) benefit for the treatment of SCI. Dermatome: an area of skin innervated by peripheral sensory fibers which travel along a peripheral
nerve that enters the spinal cord at a known level (or segment) of the spinal cord. Dermatomal Maps have been constructed for the human body to evaluate the preservation or loss of sensation throughout different parts of the body. Disk: see Herniated Disk
Dislocation: a disturbance or disarrangement in the normal (overlapping) relationship of the vertebral
bones of the spinal column (for example a facet joint dislocation). Distraction: a term for the act of pul ing apart the overlapping vertebral bones of the spinal column.
Edema: (or oedema) an accumulation of fluid, often occurring as part of the inflammatory process after
Electrophysiological Testing: the process of examining the effects (behavioral or electrical responses)
to electrical, magnetic or natural stimulation of peripheral nerves or the CNS. Electrophysiological testing can be very informative for examining nervous system function, particularly the connectivity across the damaged spinal cord. See also Evoked Potentials. EMG (or Electromyography): the recording of the electrical signals associated with the activity
(contraction) of a muscle. Evoked Potentials: the electrical signals recorded in response to the non-painful electrical or magnetic
stimulation of the brain (via surface electrodes on the scalp) or a peripheral nerve. For example, a Somatosensory Evoked Potential (SEP or SSEP) is the signal recorded from the surface of the scalp overlying the sensory cortex of the brain in response to stimulation of a peripheral nerve (e.g. a leg nerve) and tests the functional ability of CNS pathways to conduct a sensory stimulus through the spinal cord and up to the surface of the brain. A Motor Evoked Potential (MEP) is the signal recorded from a peripheral nerve or muscle in response to an electrical or magnetic stimulation of the motor cortex (via the surface of the scalp) and tests the functional capacity of CNS pathways conducting motor (movement) commands. Frankel Scale: an earlier scale for classifying severity of spinal cord injury that was modified in 1992 to
create the ASIA Impairment Scale or AIS (see above). Functional Electrical Stimulation (FES): treatment through the application of electricity to the peripheral
nerves that arise from the spinal cord. One application would be FES of specific peripheral nerves to train and enable a weak or paralyzed muscle to now make a functional and purposeful movement (e.g. phrenic nerve FES for breathing). Functional Independence Measure (FIM): records the severity of disability in people after a disabling
disorder based on 18 items. Thirteen items define disability in motor functions. Five items define disability in cognitive functions. FIM was not specifically designed for any single disability such as spinal injury. The spinal cord independence measure (SCIM) was designed to specifically record capacities after spinal cord injury (see below). Functional Recovery: an improvement in the ability to perform a physical action, activity, or task. Some
degree of functional recovery is expected to occur spontaneously after injury, but this may be very limited, particularly in sensorimotor complete (AIS-A) SCI. Gait: the manner in which a person walks, characterized by rhythm, cadence, step, stride, and speed.
Glia: usually non-impulse (no action potential) conducting cells of the CNS. Glial cells provide physical
and metabolic support for neurons. Some regulate the internal environment of the brain, especially the fluid surrounding neurons and their synapses (connections), and provide nutrition to nerve cells. Glia have important developmental roles, guiding migration (movement) of neurons to their correct location in early development, and producing molecules that modify the growth of axons and dendrites. These same functions may be important to repair after spinal cord or brain injury. There are 3 main types of glia within the CNS: astrocytes, microglia, and oligodendrocytes. Astrocytes can become inflamed (reactive) after spinal injury, which may be protective by limiting further damage, but this reactive astrogliosis may also block repair. Within the CNS, microglia have similar functions to macrophages within the bloodstream; they protect the brain and spinal cord from foreign substances and cells. They remove dead or dying cells from the CNS. Oligodendrocytes form the myelin sheaths that surround (cover) axons. Myelin speeds the conduction of impulses (action potentials) along an axon, but myelin may also restrict spontaneous growth of axons during adult life (generally a good idea). After a spinal injury, the presence of myelin may interfere with functional repair. Thus temporarily inhibiting myelin function is envisioned as a possible therapeutic target for spinal cord repair. Myelin surrounding the axons of peripheral motor or sensory axons is formed by Schwann cells, which do not inhibit axonal repair after injury. Schwann cell transplants have been thought of as a possible therapeutic strategy to facilitate repair after spinal cord injury. Good Manufacturing Practices (GMP): set of regulations, codes, and guidelines for the manufacture of
drugs (also known as active pharmaceutical ingredients, or APIs) and drug products (known as medicinal products in Europe), cells, medical devices, in vivo and in vitro diagnostic products, and foods. In the United States GMPs are referred to as "cGMPs" or "current Good Manufacturing Practices." GMP is a term that is recognized worldwide for the control and management of manufacturing, as well as quality control testing of pharmaceutical products. Helsinki Declaration: was developed by the World Medical Association and is a set of ethical principles
for the medical community regarding human experimentation. It was originally adopted in June 1964 and has since been amended multiple times. The recommendations concerning the guidance of physicians involved in medical research may be found at (also see Belmont Report). Herniated Disk: the protrusion of one or more of the spinal disks, between the vertebra, into the spinal
canal, thereby compressing the spinal cord directly or more often compressing one or more of the incoming or outgoing spinal nerve roots, which can cause numbness, pain, or muscle weakness. ICH: the International Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use. ICH brings together the regulatory authorities of Europe, Japan and North America with experts from the pharmaceutical industry to discuss scientific and technical aspects of product registration. The purpose is to make recommendations on ways to achieve greater harmonization in the interpretation and application of technical guidelines and requirements for pharmaceutical product registration. The objective of such harmonization is a more economical and ethical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines whilst maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health (
Incomplete SCI: see Complete and Incomplete SCI
International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI): A detailed
neurological assessment forms the basis for the International Standards for Neurological and Functional Classification of Spinal Cord Injury (the ASIA International Standards). They are conducted on subjects lying on their backs, and involve a qualitative grading of sensory responses to touch and pin-prick at each of 28 dermatomes along each side of the body and a qualitative grading of the strength of contraction within 10 representative (key) muscles, primarily identified with a specific spinal level, 5 for the upper extremity (C5-T1) and 5 for the lower extremity (L2-S1) on each side of the body. Microglia: see Glia.
Motor Score: based on the ISNCSCI assessment of muscle strength. The motor score is calculated by
assigning to the muscle group, innervated and primarily identified with a specific spinal level, a score between 0 (no detectable contraction) and 5 (active contraction against resistance considered to be normal with a full range of movement about the joint). C5 to T1 and L2 to S1 are tested, giving 10 levels on each side of the body for a possible maximum score of 100. The Lower Extremity Motor Score (LEMS) is a maximal 50-point subset of the ASIA motor score for the representative leg and foot muscles. The Upper Extremity Motor Score (UEMS) is a maximal 50-point subset of the ASIA motor score for the representative arm and hand muscles. Motor Level: defined as the most caudal (lowest) spinal level as indexed by the key muscle group for
that level having a muscle strength of 3/5 or greater while all key muscles above are normal (5/5). Motor-evoked potentials: see Evoked potentials
Myelin: See Glia.
Neurological Level of Spinal Cord Injury: generally the lowest segment of the spinal cord with normal
sensory and motor function on both sides of the body. However, the spinal level at which normal function is found often differs on each side of the body, as wel as in terms of preserved sensory and motor function. Thus, up to four different segments may be identified in determining the motor and sensory level and each of these segments is recorded separately. Note: the level of spinal column (bone) injury may not correlate with the neurological level of spinal cord injury. Neuron: any of the impulse or action potential-conducting cells that constitute the brain, spinal cord, and
peripheral nerves (sometimes called nerve cell). The number of neurons within the CNS is estimated to be about 100 billion. Sensory neurons relay information from sense organs (e.g. within skin and muscle) to the CNS, motor neurons carry impulses from the CNS to muscles and glands, and interneurons transmit impulses between sensory and motor neurons within the CNS (brain and spinal cord). A typical neuron consists of dendrites (fibers that receive stimuli such as synaptic inputs and conduct them toward the cell body), a cell body (a nucleated body that receives input from dendrites), and an axon (a fiber that conducts the nerve impulse from the cell body outward to the axon terminals). Both axons and dendrites may be referred to as nerve fibers. Impulses between neurons are relayed across smal gaps (synapses) by neurotransmitter chemicals released by an axon terminal across the synapse (junction between neurons or between a neuron and an effector cell, such as a muscle fiber). Large axons are insulated by a myelin sheath formed by oligodendrocytes or Schwann cells (see Glia). Neuropathic Pain: usually perceived (felt) as a steady burning sensation or "pins and needles", and/or
as an "electric shock" sensation. "Ordinary" pain stimulates only pain nerves (nociceptive neurons), while neuropathic pain often results from the activation by innocuous (normally non-painful) stimulation such as light touch, warm, or cool stimuli. After SCI, neuropathic pain can occur "above level" in a region of preserved sensation above the level of SCI, "at level" located at the level of SCI and may originate within a nerve root or the spinal cord, or "below level" also known as central pain as this definitely originates within the spinal cord or brain. A characteristic of neuropathic pain is the perception of pain in response to a normal, innocuous stimulus such as a light touch; this is called hypersensitivity or allodynia. Neuroplasticity: see Plasticity
Neuroprotection: the effect of any chemical, biological molecule or medical practice, which limits the
degree of CNS damage resulting from primary mechanical trauma or a degenerative disorder. The majority of spinal cord injuries are the result of mechanical trauma. The neurons directly destroyed by mechanical trauma are probably lost forever, but in most cases the entire cord is not completely damaged by the initial injury. Protecting any surviving cells and neural connections is a high priority target. Similar to when someone bruises the surface of their body, the initially disrupted spinal cells are known to release chemicals that can damage or destroy neighboring healthy neurons. This damage is known as secondary cell death (or apoptosis). Thus many experimental therapies are targeting the biochemical pathways responsible for secondary cell death and trying to limit their activity after spinal cord trauma. One of the limitations may be the need to stop these biochemical reactions within a very short time frame after the primary trauma (perhaps within a few hours). This is a difficult window of opportunity for a therapeutic intervention and also challenges the treatment of other CNS disorder such as traumatic brain injury and stroke. Nutraceutical: Patients have claimed benefits from alternative medical approaches although there is
often limited or no documented scientific evidence to support these claims. Nutraceuticals are non-drug (non-prescription) substances (for example, herbal medicines) that are produced in a purified or extracted form and are administered orally to provide compounds, which are intended to improve health and well-being. These substances are not always control ed or approved by a government health regulatory agency prior to or after sale. If properly labeled, they will usually have a disclaimer stating the product does not guarantee an improved health benefit. Nutraceuticals are often associated with naturopathic or alternative medicine, as is acupuncture. Oedema: See Edema
Oligodendrocyte: See Glia.
Open label: both the researcher and the trial participant know the treatment that the participant is
receiving. See also: Blinded assessments. Pain: See Neuropathic Pain
Paraplegia: the term used to refer to functional loss below the level of the upper extremities, which may
involve loss of motor and/or sensory function within the trunk and/or lower extremities (legs). This implies damage to the spinal cord below the level of T1 and may include damage to the conus medullaris or cauda equina. Peer-reviewed: a scholarly work such as a manuscript or grant application that is read and assessed by
other experts in the same field, to ensure that the author's research and claims have achieved rigorous scientific and statistical standards. Pharmacodynamics: the study of the biochemical and physiological effects of drugs in the body and the
mechanisms of drug action, including the relationship between drug concentration and effect (in brief - what the drug does to the body). Pharmacokinetics: the study of the fate of drugs in the body, with emphasis on the time required for
Absorption, Distribution within body tissues, the mode and extent of Metabolism, or breakdown and the method of Excretion. These 4 outcomes are often noted by the acronym ADME (in brief, what the body does to the drug). Preclinical: the term used to describe scientific experiments conducted prior to a human clinical trial and
may include in vivo studies of animal models of the disorder (e.g. spinal cord injury) or examination of appropriate target cells in an in vitro culture situation. Placebo: an inactive substance or treatment that has the same appearance as the experimental
treatment, but does not confer a physiological (functional) benefit for the disorder being investigated. A placebo effect is a physical or emotional change that is not the result of any physiological action of the treatment. The change may be beneficial in the short term and more accurately reflects the expectations of the participant and/or the expectations of the investigator providing the treatment (also see bias). A placebo drug or "sham" surgery can help distinguish the psychological benefits of an inactive substance from any physiological effects due to the active (experimental) treatment. Plasticity: refers to behavioral changes that occur in the organization of the CNS. Neuroplasticity can be
either positive or negative. For example, the emergence of autonomic dysreflexia or neuropathic pain can be viewed as negative changes that occur after spinal cord injury. Whereas the strengthening of synaptic connections and axonal sprouting after spinal cord injury (SCI) are changes that might lead to the formation of new neural circuits that permit the recovery of some motor function. Experiments have demonstrated improved neuroplasticity with the physical and occupational training found within active rehabilitation programs. A common and surprising consequence of CNS plasticity is that the location of a given function can "move" from one location to another in the brain or spinal cord due to repeated training after traumatic injury. The concept of plasticity can be applied to molecular and functional events. The phenomenon itself is complex and involves many levels of organization, including the expression of adaptive or alternative strategies via the appearance of newly developed neural circuits. The main thing is the adult CNS is not "hard-wired" with fixed and immutable neural connections. We simply do not know all of the conditions that can enhance neural plasticity in the intact or damaged brain and spinal cord. There is evidence that neurogenesis, the formation of new nerve cells, occurs in the adult human brain and spinal cord. Prospective: In terms of a clinical trial, it means to study the effects of an experimental treatment on a
"go-forward" basis, which is the opposite of a retrospective study which looks back historically on the outcomes of a human study. A prospective study is where the methods of data collection and analysis are specified in a protocol before the study is begun (prospective). Patients are subsequently recruited and randomly assigned to receive either the experimental or control treatment and the outcomes are collected and analyzed prospectively (in a go-forward manner). Quadriplegia: see Tetraplegia
Range of Motion: describes the space, distance, or angle through which a person can move a joint or
series of joints in their arms and legs. [p.26] RCT or Randomized Control Trial: a clinical trial in which the subjects enrolled are randomly assigned
to either the experimental treatment arm (group) or control study arm of the trial. It is the preferred clinical trial protocol to be used in all pivotal clinical trial phases (e.g. Phase 3 trials). Well-designed RCT's minimize the influence of variables other than the intervention that might effect trial outcomes. For this reason, they provide the best evidence of efficacy and safety. The most rigorous RCTs utilize a placebo (inactive) control group and blinding (conceal from trial examiners which participants have received active vs. control treatment) to minimize bias in interpretation of results. Regeneration / Repair: terms used to describe mechanisms underlying restoration of function. In the
case of CNS damage such as spinal cord injury, regeneration has been used to describe the regrowth of axons severed during spinal trauma. It was once thought that effective recovery after a cervical cord injury could only be accomplished when injured axons regenerated over long distances to the end of the cord (lumbosacral regions). It is now believed that short distance axonal sprouting across the zone of injury can be equally effective as functional "plasticity" (re-wiring) within the neural circuits below the level of injury can contribute to recovery. Repair is a more inclusive term and includes many processes that could contribute to recovery of function, including: "drugs" that stimulate axonal sprouting or the generation of new replacement cells from within the cord, the transplantation of "stem" cells, as well as beneficial reactions from CNS glia after spinal cord damage and implanted bio-compatible scaffolds. Secondary cell death: see Neuroprotection
Sensory Score: based on the ISNCSCI assessment of the patient's perception of sensation from the skin
of the body. The sensory score is calculated by testing a point on the (skin surface) dermatome associated with each spinal level from C2 to S4-5. This is done for both light touch and pinprick sensation and in comparison with sensations perceived from the skin above the level of spinal cord injury, such as the face. Each point is assigned a score from 0 (absent sensation) through 1 (impaired or abnormal sensation) to 2 (normal sensation). This gives a possible maximum score of 56 on each side, for a maximum total of 112 each for light touch and pinprick. Sensory Level: is defined as the spinal segment corresponding with the most caudal dermatome having
a normal score of 2/2 for both pinprick and light touch. [p.11] Schwann Cell: See Glia. [p.25]
Spinal Cord Independence Measure: (or SCIM) A scale for assessing function and activities of daily life
that appears to be more sensitive and accurate for assessing SCI than the Functional Independence Measure (FIM). SCIM has now gone through a few iterations (currently in version 3). The SCIM is a 100-point disability scale developed specifically for SCI with emphasis on 17 activities associated with: 1. Self-care (feeding, bathing, dressing, grooming) max. = 20 points 2. Respiration and sphincter management (breathing, bladder, bowel, use of toilet) max. = 40 points (clinically weighted) 3. Mobility (in bed, transfers, indoors and outdoors, wheelchair, walking) max. = 40 points. Sham operative procedure: a surgical procedure in which the subject is operated on but does not
receive the experimental intervention. This is the equivalent of a drug placebo treatment. Somatosensory evoked potentials: see Evoked potentials
Spasticity: involuntary increase in muscle tone (tension) that occurs following damage to the brain or
spinal cord, causing the muscles to resist being moved. Characteristics may include increase in deep tendon reflexes, resistance to passive stretch, clasp knife phenomenon, and clonus (limb movements characterized by rapid alternating contractions and relaxations of muscles). Clonus is frequently observed after SCI when the individual also has spasticity. A more scientific definition of spasticity is a velocity-dependent, increased resistance to passive muscle stretch. In other words, when a spastic muscle is stretched, it is harder to move the muscle than normal, and the faster the muscle is stretched, the harder the muscle is to move. Stem or Progenitor Cells: Cel transplantation has been extensively reported by the popular media as a
universal treatment for all manner of il ness or injury. While tremendous progress has been achieved for certain simple tissues and their associated disorders and diseases, including bone, muscle and blood, the routine use of cell transplants for CNS disorders is still in early development. Unfortunately, because generating cells for transplantation is a relatively easy procedure, several unscrupulous clinics have been offering surgical treatments with cell injections, even though there is no validated evidence for benefits from these procedures. As can be appreciated the CNS is the most complex organ of the body containing thousands of uniquely identifiable cell types. Most transplanted cells are likely to only differentiate (change into) a few types of adult neurons and glia. Thus what type of cells and how many cells should be transplanted are still unanswered questions. When do we transplant after injury, where do we transplant and how do we protect the transplanted cells from being rejected by the host CNS. Every simple answer triggers dozens of further questions. What follows is a very short and incomplete explanation (for further details, please consult documents available on the International Spinal Cord Society (ISCoS) website ( ‘True' stem cells have the potential to self-renew indefinitely and differentiate (develop) into numerous types of cells. In practice most cell transplants do not involve ‘true' stem cells. In reality, they are progenitor cells, which come from stem cells. However the term stem cell has entered popular folklore and is commonly used for all transplanted cells. Progenitor cells have less plasticity than ‘true' stem cells and a more limited capacity to differentiate. Once CNS cell transplant procedures have been developed and refined, the potential benefits of stem cells are numerous and include: replace lost cells due to injury or disease, provide substrate or scaffold for axonal outgrowth to create novel neural connections, limit detrimental inflammation and reduce secondary cell damage, promote blood vessel formation, and/or release beneficial cytokines and growth factors. Of course, with any emerging technological advance there a number of unknowns or concerns with a premature application of cell transplants after spinal cord injury and these include: a very incomplete understanding of the benefits and risks in preclinical animal studies, poorly defined cell products (some with no GMP protocols or standards), additional damage to cord if cells have to be injected directly into the spinal cord tissue, stimulation of neuropathic pain, and/or causing the formation of cancerous tumors since some stem or progenitor cells can rapidly divide. Surrogate endpoints: A measurement of an expected biologic activity from the experimental drug or cell
transplant that substitutes for the clinical (functional) endpoint. A surrogate endpoint (outcome) may predict a patient's final clinical outcome. A surrogate marker (measure) may indicate whether a drug is effective without having to wait for the longer-term functional clinical endpoints being achieved. The identification of an accurate surrogate measure or marker can reduce the time required in an early clinical trial phase to show a possible benefit. Surrogate endpoints can and have been used in Phase 2 clinical trials. Synapse: the cell membrane of the signal-passing neuron (presynaptic neuron) comes into close
apposition with the membrane of the target (postsynaptic) neuron. Both the presynaptic and postsynaptic sites contain receptors and molecular machinery necessary for synaptic communication between the two neurons. the presynaptic part belongs to an axon terminal, while the postsynaptic element is usually a dendrite or soma of the second neuron. It should be noted that many neurons can receive and integrate inputs from thousands of presynaptic neurons and project to several hundred other neurons. In short, every neuron is presynaptic to some neurons and postsynaptic to other neurons. In a chemical synapse, the presynaptic neuron releases a chemical called a neurotransmitter that binds to receptors located in the postsynaptic cell, usually embedded in the plasma (cell) membrane. The neurotransmitter may activate a receptor-ion channel complex directly or an indirect second messenger pathway that either excites or inhibits the postsynaptic neuron. The number of neurons is estimated to be 100 bil ion and the number of synaptic connections in the average adult brain is truly astronomical and defies comprehension (approximately 250-500 trillion). Tetraplegia: (also known as quadriplegia) refers to loss of motor and/or sensory function in all four limbs
due to spinal cord damage, with impairment of the upper extremities as well as trunk, legs and pelvic organs. This implies damage to the cervical spinal cord (at or above the T1 level). Technically tetraplegia is the more correct term, because "tetra", like "plegia", has a Greek root, whereas "quadra" has a Latin root and in classic naming terminology you do not mix Latin with Greek words! Zone of Partial Preservation (ZPP): only used when SCI is complete and refers to those segments
below the neurological level of injury where there is some preservation of impaired motor or sensory function (usually, but not always, within a few segments of the neurological level). APPENDIX D: Selected websites (listed alphabetically)
NOTE: each site has multiple links for further information
Academy of Spinal Cord Professionals (ASCI American Spinal Injury Association (ASIA China Spinal Cord Injury Netw Christopher and Dana Reeve Foundation: Craig H. Neilsen Foundation elearnSCI (online information on SCI care and treatment ): European Multicenter study about Spinal Cord Injury (EMSCI European Spinal Cord Injury Federation: Fondation internationale pour la recherche en paraplégie (Switzerland): Institut pour la Recherche sur la Moëlle épinière et l'Encéphale (France) ICORD (International Collaboration on Repair Discoverie International Society for Stem Cell Research (ISS International Spinal Cord Society (IS International Spinal Research T Japan Spinal Cord Foundation: Miami Project to Cure Paralysi Neil Sachse Foundatio NINDS Spinal Cord Injury Information Page Paralyzed Veterans of America Rehab. Research & Train Center (RRTC) on Secondary Conditions (USA Rick Hansen Foundation (Canada) SCIRE (Spinal Cord Injury Rehabilitation Evidence SCOPE (Spinal Cord Outcomes Partnership Endeavo Spinal Cord Injury Canada Spinal Cord Injury Network (Australia Spinal Cure (Australia): United Spinal Association (USA) APPENDIX E: Selected references

NOTE: These publications are primarily directed to a clinical and scientific audience

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Bracken MB, Shepard MJ, Collins WF, et al. A randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury: results of the second national acute spinal cord
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Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the third national
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Buchholz AC, Martin Ginis KA, Bray SR, et al. Greater daily leisure time physical activity is associated with lower chronic disease risk in adults with spinal cord injury. Applied Physiology, Nutrition, and
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Casha S, Zygun D, McGowan MD, et al. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain 2012; 135: 1224-1236
H S Chhabra, C Lima, S Sachdeva, et al. Autologous olfactory mucosal transplant in chronic spinal cord injury: an Indian Pilot Study. Spinal Cord 2009; 47: 887–895
Dobkin B, Apple D, Barbeau H, et al. Weight-supported treadmill vs over-ground training for walking after acute incomplete SCI. Neurology 2006; 66: 484-93.
Finnerup NB, Baastrup C. Spinal cord injury pain: mechanisms and management. Current Pain
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Geisler FH, Dorsey FC, Coleman WP. Recovery of motor function after spinal cord injury: a randomized, placebo-controlled trial with GM-1 ganglioside. New England Journal of Medicine 1991; 324:1829-
Geisler FH, Coleman WP, Grieco G, Poonian D. The Sygen multicenter acute spinal cord injury study. Spine 2001; 26: S87-S98.
Heinemann AW, Steeves JD, Boninger M, et al. State of the science in spinal cord injury rehabilitation 2011: informing a new research agenda. Spinal Cord 2012; 50: 390-397.
Hurlburt RJ, Hamilton MG. Methylprednisolone for acute spinal cord injury: 5-year practice reversal. Canadian Journal Neurological Sciences 2008; 35: 41-45.
Illes J, Reimer JC, Kwon BK. Stem cell clinical trials for spinal cord injury: readiness, reluctance,
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Jacobs, PL, Nash, MS. Exercise recommendations for individuals with spinal cord injury. Sports
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Kwon BK, Okon EB, Plunet W, et al. A systematic review of directly applied biologic therapies for acute spinal cord injury. Journal of Neurotrauma 2011; 28: 1589-610.
Lammertse DP, Jones LA, Charlifue SB, et al. Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial. Spinal
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Mackay-Sim A, Féron F, Cochrane J, et al. Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain 2008; 131: 2376-86.
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Steeves JD, Lammertse D, Curt A, et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP Panel: Clinical trial outcome measures. Spinal Cord 2007; 45: 206-
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Catalogo farg:layout

CATALOGO GENERALEGENERAL CATALOGUE made in Italy, made in F.A.R.G. Nei primi anni Sessanta ad Invorio, nella provincia di Novara, da sempre distretto di eccellenza nella produzione dell'industriadella rubinetteria, Giampiero Conton inizia la sua attività fondando la Rubinetteria Conton. Inizialmente l'azienda ebbe comescopo principale la commercializzazione di materiale idrosanitario; l'intuito del fondatore e alcuni segnali provenienti dallaclientela fecero capire le aperture del mercato e la possibilità di investire con ottimi risultati nella produzione di rubinetti agalleggiante con relative sfere in materiale plastico e in rame, senza dover fare i conti con una concorrenza troppo numerosa.E' nel 1996 che nasce F.A.R.G., naturale evoluzione di Rubinetteria Conton, che opera oggi su un'area di circa 15.000 mq dicui 5.000 mq coperti dedicati ai processi produttivi. Nel tempo la gamma dei prodotti si è ampliata con l'introduzione dialcuni componenti per impianti idrosanitari mantenendo la garanzia di qualità attestata da una produzione interamente ‘Made in Italy'. La costante attenzione della qualità, l'utilizzo di tecnologie avanzate e una rete di vendita che si avvale dellacollaborazione di agenti presenti sul territorio, hanno portato l'azienda a imporsi sul mercato nazionale e su quello estero.


Endometriosis and Infertility Epidemiology and Evidence-based Treatments EBIHA OZKAN,a WILLIAM MURK,b AND AYDIN ARICI aDepartment of Obstetrics and Gynecology, Kocaeli University School of Medicine, bDepartment of Obstetrics, Gynecology and Reproductive Sciences, Yale University

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