Clinical Trials Advice from ASIA
After a spinal cord injury (SCI), patients are sometimes told there are no drug or cell transplant treatments available that will repair their damage. This is still true, and the advice is given to persuade people to actively focus on their rehabilitation rather than hoping for a miracle cure.
Nevertheless, the science of spinal cord repair is progressing rapidly and several treatments that may improve the functional capacities of people with spinal injury are now entering clinical trial programs. The broad therapeutic goals, treatment timelines, and possible underlying mechanisms are listed below.
Surgical Intervention
One of the primary goals after SCI is to limit further damage. Often the trauma has resulted in the bones of the spinal column being moved out of place or shattered, resulting in compression of the spinal cord tissue. To remove any harmful pressure and limit any subsequent spinal cord damage, surgeons will remove threatening bone fragments, realign the vertebrae and use appropriate “cages”, rods, and screws to rigidly stabilize the vertebral column. The available evidence suggests that this surgery should be done as soon as it is medically safe and feasibly possible, often within the first 24 hours after SCI.
At more chronic stages (usually not before one year after SCI) tendon transfer surgery can also provide some functional benefits to people living with SCI. This can greatly enhance the quality of life for patients with tetraplegia by enabling them to do more tasks independently, but the surgery is difficult to reverse and would interfere with any spontaneous recovery after SCI, which is why most tendon transfer surgery is not performed while there is still the possibility of further spontaneous
recovery. Tendons are the strong cords that connect muscle to bone. When
a tendon crosses a joint, it helps transmit a muscle contraction into movement of the joint. A tendon transfer repositions the tendons of a working muscle (such as that within the upper arm) so that they take over the functions of a paralyzed muscle. This enables the intact working muscle to do what the paralyzed muscle can no longer do. For example, in the upper arm, the triceps muscle is used to straighten the elbow. Normally the deltoid (shoulder) muscle pulls the arm backwards and forwards away from the body. If the triceps muscle is paralyzed, but the deltoid is still functional, surgeons can split the deltoid muscle and attach (graft) a portion of the deltoid tendon to the triceps. This restores elbow function without greatly diminishing the function of the deltoid.
Tendon transfer surgery can help restore capabilities of the upper extremity that are necessary for self-care and increased independence:
Ability to straighten (extend) and bend (flex) the elbow
Ability to bend and straighten the wrist
Ability to grip with the fingers and hand
Rehabilitation Strategies
Subsequently, active physical and occupational rehabilitation strategies have been documented to facilitate improved recovery of functional capacities. Ongoing investigations are refining these rehabilitation prescriptions for each severity of SCI, segmental level of SCI, and time since SCI (for reference see SCIRE document – spinal cord rehabilitation evidence at www.icord.org).
Robot assisted movement of arms and legs is a novel intervention currently being investigated in a number of centers across the globe. When combined with virtual reality environments (e.g. video games) these rehabilitation activities can be highly enjoyable and motivational to the participant, ensuring they maintain an ongoing rehabilitation program.
Engineered approaches have also provided many valuable devices to assist a person living with SCI. Wheelchairs come in all sorts of shapes and varieties to meet the varying demands of the user. Functional electrical stimulation (FES) has been successively used to activate paralyzed muscles in a controlled manner. Stimulators have been directly implanted onto the diaphragm of patients requiring 24/7 ventilator support to breathe. This has enabled these individuals to be free of a tracheostomy and breathe without the need of a ventilator Perhaps more importantly, it has restored the individual’s sense of smell. There is likely no limits on what can be achieved or replaced by an engineered device, even though most people would prefer function to be restored biologically.
Why are clinical trials necessary?
It can be surprisingly difficult to find out if a treatment is safe and valid. There are two main problems.
- The placebo effect. People with spinal injury are desperate to get better. After being given a treatment their belief and hope usually leads them to report an apparent improvement. In clinical trials, patients receiving a sham or placebo treatment often report a considerable improvement in their condition, and this may be just as large an improvement as is reported by the patients receiving the experimental (sometimes called active) treatment.
- Spontaneous recovery. Immediately after a spinal injury many patients are often completely paralyzed or have severe sensory and motor deficits. However, most people will recover some additional function, even without treatment. The rate of recovery is greatest in the first three months, but continued recovery has been observed for a year or even more. It is very difficult to work out whether any functional improvement in an individual is due to this spontaneous recovery, or due to the effects of a treatment, particularly if the treatment is given soon after the injury.
Why you should think before accepting an experimental treatment?
People with spinal injuries are understandably interested in recovering improved function. Scientists have been working extremely hard to develop new treatments, and want very much to see their treatments help people with spinal injuries as soon as possible. The majority of clinical trials will be well planned and carefully conducted. However there may be a few that should be avoided until there is better evidence that they provide a meaningful benefit.
A good clinical trial program will be carefully designed to compare a group of patients receiving the experimental treatment with others receiving no treatment or an inactive placebo. The only type of trial in which this is not the case is where patients whose condition (functional capacity) is very stable (this usually means patients 1 year or more after spinal injury) who act as their own control group, and are given a treatment to see whether their condition improves compared with their previous capacities.
Experimental treatments offered without having completed a trial. In the absence of a clinical trial in which the effects of the treatment are compared with a control group of patients receiving a placebo treatment, it is almost impossible to determine whether the treatment is really effective. Unfortunately, where patients are desperate for a cure, there is the opportunity for less scrupulous organizations to offer unproven treatments to those who can pay. You should NOT have to pay for any procedure specifically related to a clinical trial program, but you, or your health care insurance system, may have to pay for the current standard of medical care.
Essential Regulatory Requirements for any Human Study to Be a Valid Clinical Trial
Randomization of a sufficient number of appropriate participants to
experimental group and (suitable) control group
Independent assessment of outcomes by examiners “blinded” to which
group the subject was assigned
Sufficient long-term assessment of trial participants (up to 12
months)
No payment to study investigators or fee paid by participants (thus,
cell transplants offered by for profit clinics in a number of
countries are not clinical trials).
How are clinical trials structured?
It takes three clinical trial steps, or phases, to qualify a treatment for clinical use in human patients (see below).
Phase 1 is to find out if the treatment is safe. A fairly small number of patients, usually between less than 50, are given the treatment, usually initially at a low dose, to determine that it is safe with no side effects.
Phase 2 is another early phase study where a small number of subjects (usually < 100) are assessed for whether the treatment stimulates positive biological or functional effects in comparison to subjects receiving the treatments with a control group.
Phase 3 is a pivotal human study to extend and confirm the potential beneficial effect observed in Phase 2. Here a large number of patients, usually in several clinical centers, are given the active treatment or the inactive placebo control treatment. If the active treatment demonstrates a clear clinical benefit with no serious side-effects, it will be approved by the national regulatory agencies for use as a treatment for that specific therapeutic target or clinical condition (note: sometimes two independent phase 3 trials are required to achieve regulatory approval).
Design of clinical trials:
The key feature of most clinical trials is the comparison of a group of patients receiving the active (experimental) treatment with a control group, that either does not receive the treatment or receives an inactive placebo treatment. When the effect of a treatment on the experimental group is being compared with the outcomes from a control group, steps should be taken to make sure that the people doing the assessments are unaware of whether patients have received active or dummy treatments (this is known as blinding).
How would participation in a clinical trial affect you?
Not all patients will qualify for a trial, because most trials will select particular groups of patients with particular types of spinal injury. All trials have criteria because if the patients are too different from one another it may be impossible to find out if a treatment has worked. After enrolment, patients are randomly assigned to the active treatment or control group. After or during the treatment, there will be frequent follow up examinations, for which it will be necessary to attend the clinic. These examinations may include a full physical exam, blood tests, and tests of the ability to perform daily living tasks to assess spinal cord function. You should NOT have to pay for these visits.
What if you get assigned to the control group?
Most patients would obviously prefer to receive the active treatment. However, as we described above, it is impossible to decide if a treatment really works unless there are control patients with whom to make comparisons. If by mischance the treatment has an undesirable side effect, then being in the control group is an advantage. Patients participating in a trial should all benefit by receiving the current best care.
What should you expect after a clinical trial?
At the end of the trial you are unlikely to be completely cured. Could you then obtain another treatment in a different trial? The enrolment criteria for some trials may exclude patients that have already received some types of experimental treatment.
What is informed consent?
Before entering any trial you or your relatives will have to give informed consent. Here are some of the things about which you should satisfy yourself.
Experimental evidence that the treatment works; Any treatment reaching clinical trials should have been tested in animals with spinal injuries, and should have produced a clear improvement without toxic side effects. It is important that this positive result has been published and reviewed by other scientists, and has been repeated several times, in different types of experimental spinal cord injury, and in more than one laboratory. If you ask you should receive a detailed account of this work. Alternatively, a treatment may be entering a spinal cord injury trial based on its prior safe clinical use and benefit for a disorder that has similar etiology or pathology.
Evidence that the treatment is safe: Before being applied to human patients any treatment should have gone through a series of safety tests. It may have already been tested in Phase 1 or 2.
Design of the trial: You should know whether you being enrolled in Phase 1, 2 or 3. The trial should be registered with an appropriate government regulatory body (e.g. www.clinicaltrials.gov). In a well conducted Phase 2 or 3 trial there will be a treatment and control group, and patients will be randomly assigned to one or the other. Steps should be taken to blind the assessors as to whether you are in the treatment or control group. There will be a number of follow-up examinations over a period, often as long as a year after the treatment, conducted in the appropriate clinic. You should not have to pay for these. At the end of the trial there should be a clear policy on what can be offered to patients in both the active treatment and control groups.
Selected Past Trials (directed to recovery of sensory-motor function)
- Methylprednisolone sodium succinate (MPSS)
Anti-inflammatory corticosteroid, providing neuroprotection to limit further secondary damage after initial injury. Several large phase 2 and phase 3 trials in 1980s suggested a possible small benefit. No regulatory approval, but, sometimes used as an off-label treatment option if given within 8 hours of SCI. High dose MPSS can cause some adverse events such as sepsis and pneumonia. - GM-1 Ganglioside (Sygen)
Suggested to provide neuroprotection, but exact mechanism has not been clearly defined.
Large phase 3 trial during the 1990s missed statistical significance.
Suggested that the study set the trial outcome threshold too high (an increase of 2 AIS grades was set to show clinical benefit).
Formulation is difficult to find and thus rarely used as a treatment option. - NMDA antagonist (GK-11)
Suggested to act as a neuroprotective treatment for acute SCI, if provided within 2 hours of injury.
Missed statistical significance when compared to placebo control subjects.
May have set primary outcome threshold too high. - 4-aminopyridine (Fampridine)
Well established mechanism is the blockade of voltage sensitive potassium channels that repolarizes neuronal membrane after activation.
Administration of Fampridine will prolong activation of excitability of neurons thereby improving conduction of action potentials along any axonal fibers that have been preserved after initial injury (majority of SCI does NOT disrupt all connections across spinal injury).
Suggested that administration after long term survival with SCI would allow hypo-active spared fibers to recover transmission and improve functional capacities.
Phase 3 study missed statistical significance when compared to placebo controls, however Fampridine appears to benefit long term multiple sclerosis survivors. - Autologous activated macrophages (Procord)
transplantation of a patient’s own macrophages, which are then activated by exposure to a skin sample).
Suggeted to act as a neuroprotective and/or therapeutic promoting axonal outgrowth.
Surgical transplantation, directly into SCI site was completed within 14 days of acute injury.
Phase 2 results showed no benefit over sham-operated control subjects. - Olfactory Ensheathing Glia (OEGs)
OEGs suggested to be a supportive cell for the growth of olfactory sensory neurons, which grow from the nasal mucosa into the olfactory bulb of the brain on a regular basis throughout adult life. Nevertheless, preclinical studies in animal models of SCI has been unable to consistent demonstrate a therapeutic benefit for OEG transplantation.
Phase I/IIa Australian study involved a half dozen chronic SCI subjects, which demonstrated safety of autologous (patient’s own) OEG transplants in 3 experimental subjects living with chronic complete thoracic SCI, but no efficacy of the surgical procedure. - Spinal Cord Injury Locomotor Training (SCILT)
To improve functional ambulatory capacity after (sensory-motor) incomplete SCI.
Compared subjects undergoing body weight-supported treadmill training to control subjects receiving more conventional, but enhanced, physical therapy.
No statistically significant differences between two groups, Further studies underway to confirm or outline under-appreciated benefits of various activity-dependent rehabilitation strategies.
What lessons have been learned from past trials?
First and foremost, the human studies (listed above) were all conducted in a rigorous and objective manner. The trials were all adequately powered with an appropriate number of subjects for the trial phase being conducted. They used “blinded” assessments and tracked trial outcomes over a sufficiently long recovery period (usually at least 6-12 months). Finally, no subject was charged for participation in a trial, nor did any investigator receive payment for conducting the study.
Some of the clinical studies had sufficient preclinical data to justify a human study (e.g. Fampridine), although some might argue that this was not the case for other therapeutic interventions (e.g. Sygen). Insufficient preclinical data or a lack of prior clinical experience with the therapeutic can make it very difficult to understand or interpret negative clinical trial results.
The degree of spontaneous (untreated) recovery can be larger than expected and should be well understood for each type of SCI being included in a human study. Such an appreciation is essential for setting accurate and meaningful outcome thresholds for what is likely to be a realistic, but statistically significant, difference between an experimental and control group. Some of the previous clinical trials may have failed because they set too high an expectation for a therapeutic benefit and consequently the therapy may have been abandoned prematurely. Recently, renewed efforts have centered on defining objective clinical trial outcome tools that are sensitive (to show subtle effects), accurate (specific to the target of the therapy) and reliable ( in the hands of trained evaluators).
Several of the trials had broad inclusion criteria (i.e. they combined very severe with less severe types of SCI in their analysis). In short, different types of SCI could have opposite responses to a therapeutic and statistically cancel each other out. This reduces the ability to detect small, but potentially significant, benefits. What has been taken forward is the need to characterize and stratify participants carefully and make every effort to enrol similar (homogeneous) subjects, especially in early phase studies.
Note: the information below is subject to change quickly and thus may not be current. Many trials can be delayed by a shortage of funds to undertake the study.
Many early phases of a clinical trial program are often listed as Phase 1/2a, which means that they are primarily a Phase 1 safety trial, but some very preliminary functional outcome data will also be collected. Also note below that some of the described trials are indicated as Pre-Phase 1/2a, which means they are in the late stages of planning and have not as yet enrolled subjects in the study. All of the examples listed below have been presented to the appropriate regulatory agency having jurisdiction over the location for the trial. Finally, no therapeutic intervention is approved for clinical use until it has completed at least one Phase 3 trial.
Pre-Phase 1/2a – Riluzol
Multiple cellular actions, such as sodium channel blocker and NMDA receptor antagonist. A large activation of NMDA receptors by excitatory amino acids (released from cells after mechanical trauma) can lead to the detrimental excitation of spinal neurons and even cause them to die.
Riluzol is suggested to reduce the activation of NMDA receptors and thus act as a neuroprotectant.
Riluzol has previously been approved as a treatment option for amyotrophic lateral sclerosis (ALS) and thus is an example of an SCI experimental therapeutic arising from a previous clinical application The proposed location for this trial is Canada and the USA with a projected start date in 2010.
Pre-Phase 1/2a – Human Schwann cells
Schwann cells are found within the peripheral nervous system (nerves to and from the spinal cord and brain). Schwann cells are glial cells that wrap tightly (myelinate) around axons of sensory and motor neurons to improve conduction of action potentials to and from the various organs (e.g. muscles). Schwann cells also guide the development of axons towards their appropriate targets (e.g. muscle fibers) during development and after injury to peripheral nerves. Preclinical studies suggest that Schwann cells may aid in the support and guidance of re-growing (regenerating) central nervous system axons after SCI.
The proposed location for this trial is the USA with a projected start date in late 2010 or early 2011.
Pre-Phase 1/2a – human embryonic stem cell (hESC) oligodendrocyte progenitor cells (OPCs)
Developed to promote remyelination after acute SCI Similar to peripheral Schwann cells, Oligodendrocytes within the brain and spinal cord myelinate long axons.
After SCI, the myelin is often lost (demyelination),including the myelin wrapped around any spared (uninjured) axon fibers. This slows or interrupts conduction of action potentials along these preserved fibers and may underlie loss of function.
Based on preclinical studies, the prevailing hypothesis is transplanting these hESC-OPCs within 2 weeks of acute human SCI will maintain myelination or re-myelinate spared axons and thereby preserve function or promote improved recovery.
The proposed location for this trial is the USA with a projected start date in late 2010 or early 2011.
Phase 1/2a – Erythropoietin (EPO)
EPO has a diverse number of actions including possible action as a neuroprotective intervention; however, preclinical studies have not reached a consensus on its benefits after SCI.
There is universal agreement that any EPO effects are contraindicated when given with or shortly after methylprednisolone.
Currently an early phase acute SCI study is underway in Italy. Italy is one jurisdiction where methylprednisolone is routinely administered after acute SCI!
Phase II – Lithium
Principal cellular action is as a sodium channel agonist (acts like sodium to activate neurons).
Long-term clinical psychiatric use for bipolar disorders, but now suggested to provide neuroprotection and/or promote functional repair after acute SCI.
As yet unpublished findings from a Phase 1 dose response human study in the People’s Republic of China (PRC) has determined the oral doses that are tolerable after SCI.
Proposed trial location is the PRC with a commencement date of late 2010.
Phase II – Minocycline
Second generation tetracycline which is now off-patent.
Minocycline has antibiotic actions, as well as anti-inflammatory effects. It has long been used as a medication for acne.
Phase 1 study in Canada suggests minocycline is safe after SCI and may have neuroprotective benefits if administered within 12 hours of acute SCI. Phase I/IIa showed promise in small 50 patient study.
Proposed trial location is Canada and expected to start in late 2010.
Phase II – Cethrin
Inside all cells, a number of protein enzymes are involved in translating signals from the external surface of cells. These second messenger systems such as the Rho-kinase pathway are involved in the growth of axons , including regeneration of axons after injury.
Cethrin interacts with these kinases and preclinical evidence suggests Cethrin has neuroprotective and/or axonal sprouting effects.
Phase 1 study demonstrated safety and suggested some possible benefit.
Proposed trial location is Canada and USA and expected start date is 2010.
Phase II – ATI-355
ATI-355 is a humanized antibody against central nervous system myelin. In preclinical studies it is known as anti-NOGO.
A large number of preclinical studies have established central nervous system myelin as a non-permissive substrate for axonal growth. For example during development, all central neurons grow and make connections in the absence of myelin.
ATI-355 is suggested to act as an axonal sprouting therapy for acute SCI (< 14 d).
Phase I study has demonstrated safety and developed preferred administration protocol within 14 days of acute SCI.
Phase II is underway in Europe.
Numerous treatments, primarily involving cell transplants of various types are currently being offered for a fee in several private clinics throughout the world. The cells that are supposedly transplanted are usually purported to be embryonic, stem, or progenitor cells; however, independent characterization of the type of cell has rarely been completed or confirmed. The required payment can vary from $20,000 to $100,000 for each surgical procedure and often it has been suggested that multiple treatments are required, as well as extensive rehabilitation therapy which the patient must also pay.
To date, NO cell transplant procedure for SCI or any other neurological disorder has completed a valid clinical trial program. The only valid human cell transplant study for SCI was a very small Phase 1 trial undertaken in Australia, which showed no benefits for the procedure and has not been extended to the required pivotal Phase 3 trial stage. Furthermore, there is no scientific consensus on any preclinical data demonstrating a particular embryonic, stem, or progenitor cell that can be successfully used to improve functional outcomes after SCI.
Thus at this time, ASIA cannot recommend any patient should pay for a cell transplant procedure until it has successfully completed a valid clinical trial program.
Here are some questions to pose to any researcher inviting you to participate in a human study. This checklist may assist you in your decision whether or not to participate.
- Safety
- Are there safety risks associated with this experimental treatment?
- If so, can you describe the possible risks associated with this experimental treatment?
- Could my condition or my health get worse after this experimental treatment?
- Possible benefits
- Can you describe the possible specific benefits of this experimental treatment?
- Can you describe the maximum level of recovery I might see after this treatment?
- Can you describe how any potential benefit will be measured and validated?
- Preclinical or prior clinical evidence
- Can you describe the preclinical evidence (e.g. in animals with SCI) or prior clinical experience that suggests this experimental treatment may be beneficial?
- Have the preclinical findings been independently replicated?
- If they have been replicated, is there a consensus among the scientists that this treatment addresses a valid therapeutic target for improving my functional outcomes?
- Are there any dissenting opinions for not going forward with this treatment?
- Clinical trial protocol
- Is this human study registered as a clinical trial with an appropriate qualified regulatory body?
- Can you describe what clinical trial phase this particular human study falls within?
- Is there a control group in this study?
- Could I be randomly assigned to the control group?
- Can you tell me how long I will be assessed for any change in outcome?
- Will I be blinded to whether I have received the experimental or control treatment?
- Will the investigators and examiners be blind to what treatment I have received?
- Participation in other trials
- Could my participation in this clinical trial limit my participation in other SCI clinical trials?
- 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?
- Payments and costs
- Do I have to pay for this treatment?
- Are there any other costs associated with my participation in this study?
- Will my expenses associated with participating in this study be paid (e.g. travel to center for follow-up assessment)
- Independent assessment of the treatment and investigator
- 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?
Reasonable Answers (that should be expected from an investigator) can also be provided to any of the above questions
