Written by Dr Sarah Yates, Director of Scientific Affairs, Muscular Dystrophy Campaign Treatments are the goal of our research programme and the focus of most of our fundraising. So what is the procedure when new treatments emerge from the laboratory ready for testing on humans? Clinical trials are designed to answer some fundamental questions: How effective and safe is the treatment and what are the side effects? Does it work in humans and, if so, how efficiently does it prevent or improve symptoms? What dosage levels should be administered? The standard model adopted when a new treatment is tested follows three consecutive stages known as Phases 1, II and III. Any therapy which is on the brink of the first small-scale human trials will have already undergone a long period of development and testing in the laboratory. Gene therapy for Duchenne muscular dystrophy is still at the developmental stage. When scientists believe their work is ready and the potential treatment has been successful in alleviating the symptoms of animal models, they publish their results. Based on these, clinicians then decide whether to run Phase I trials. First they must get permission from their hospital ethical boards or in the case of gene therapy from GTAC (the Gene Therapy Advisory Committee). Medical research institutions may have to start off funding the trials but it would be hoped that the NHS, biochemical or pharmaceutical firms would take up the cost later on. Phase I Trials Phase I trials are pilot studies. They are the first time a new treatment is administered to humans. Their purpose is to determine how safe the treatment is, and whether it is tolerated and behaves in the way predicted by all the previous experimental investigations. Initial doses are the lowest possible consistent with obtaining the required information but may gradually be raised to the required dosage level. The number of participants at this stage is very small. All those who are asked to join a trial are protected by regulations governing their participation. They must be fully informed and have had ample opportunity to ask questions and to think about their decision. All participants are free to leave a trial at any time without giving a reason, or can refuse to join it in the first place without jeopardising any other treatment they should be receiving. They have to sign a lengthy consent form confirming that all this has been made clear to them. Clinical trials have to be exceptionally carefully set up and controlled and run. Only then will there be broad agreement amongst clinicians and scientists based on reliable information. In the early 1990s the American scientist Dr Peter Law considered that myoblast transfer (the implantation of billions of healthy muscle cells) merited testing on humans. He set up a project to inject myoblast transfers into the big toes of boys with Duchenne muscular dystrophy. The results, he claimed, were very encouraging. Other clinicians and scientists had grave reservations about the validity of the trials which they believed to be premature and poorly structured. The Muscular Dystrophy Campaign in the UK advised families against going to the USA to take part. Additional trials were organized by other doctors in the USA to check Dr Law’s findings. Most came to a halt and the rest do not look promising. A recent independent check has found no evidence of muscle derived from transplanted myoblasts in a patient treated by Dr Law’s team. Phase II trials These can start if Phase I results are satisfactory. They are the first in which the disorder is actually properly treated. Different dosages may be given to different patient groups to establish whether the treatment is suitable for further study or should be abandoned. Patient numbers in these trials are usually small. Phase III trials In the final clinical trials, the treatment is likely to be compared with an inactive medication called a placebo and possibly with another standard treatment already used for the disorder under investigation. Patients are allocated randomly to one of the groups and during the trials neither the doctor nor the patient knows which preparation is being given. This is known as a double blind trial. Phase III usually involves much larger numbers of patients so that the results can be analysed statistically. Sometimes we hear of amazing breakthroughs in other countries whose standards may not be as rigorous as in the UK. For example, a treatment which is claimed to slow the progression of Duchenne muscular dystrophy may have been tried on patients who actually have Becker muscular dystrophy. British scientists and clinicians are at the leading edge of research and management of neuromuscular conditions in the world. If a viable treatment from abroad does look likely, they will know about it and act on it. Usually trials are conducted to internationally approved standards which means these are transferable between countries, though there may still be differences of opinion between the regulatory boards of different countries. If a condition is severe enough and the treatment looks very promising, Phase III trials might be accelerated to make the treatment available to doctors quickly. Treatments don’t always come in the form of original drugs or untried techniques such as gene therapy. Sometimes a drug which is already known to be useful in treating one disorder will be tried on another. A myasthenia gravis trial underway in Britain is a case in point. Usually people with myasthenia gravis are started on a drug called anticholinesterase which manipulates the chemicals at the acetycholine receptor, the site where things go wrong. When this drug is not as effective as it could be, the patient is put on coffico-steroids on various dosages usually for life. The commonly used steroid is prednisolone which has side effects over time. Another agent, azathiaprine, has been used on occasions in myasthenia gravis and has been very useful in treating other disorders. Dr Jackie Palace and Professor John Newsom-Davis at the Radcliffe Infirmary, Oxford set up the trial because they wanted to know for sure whether azathiaprine should be prescribed automatically with prednisolone or if it should be used only when prednisolone starts to fail. The trial is a ‘multi-centre trial’ in which other neurology centres are participating. It is designed to answer further questions: If patients are on azathiaprine, do they require lower doses of steroids? Do they suffer fewer relapses? Are the side-effects different or reduced? Do dosage differences affect the strength of the patients? This is a three-year trial because the long-term effects of the treatments have to be monitored. It is also a double blind trial: the patients don’t know what treatment they are getting, and the doctors don’t know which treatment they are giving. A statistical trial centre plays a crucial role here. When a trial is set up, the names of participants are forwarded to the centre which divides them randomly in half. Each patient is tagged with a code and the centre then instructs the pharmacy to make up the drugs against these code numbers. The clinician administers drug X to patient X without knowing whether the drug is a placebo or not, or in the case of the myasthenia gravis trial, without knowing whether prednisolone is being administered alone, or with azathiaprine. Both azathiaprine and prednisolone are ‘toxic’ drugs; they have side-effects as most drugs do. However, there is another trial currently underway for McArdle’s disease which is investigating a substance that is safe, has no side effects, and is available cheaply. So why not advise patients to take it anyway? Why bother to conduct trials if we are satisfied about safety? In fact it is pointless to administer any therapy unless it works. Prescribing treatments which turn out not to have any effect raises false hopes and causes patients to lose faith in future therapies. Even if the substance is useless and harmless, it may interact badly with other drugs. If the substance can relieve symptoms, it is important to establish correct dosages and regimens scientifically rather than through guess-work. And if a treatment (albeit useless) is already being prescribed, alternative trials for other useful potential treatments may not go forward. McArdle’s disease is a glycogen storage disorder which interferes with the body’s ability to process fuels that supply energy for muscle work. The condition can cause considerable disability. The substance under investigation is thought to prevent the muscle pain, cramps and fatigue that are a consequence of exercise. Run by Professors Richard Edwards and Bob Beynon and their colleagues at a university institute in Manchester and at the University of Liverpool, the trial will be a double-blind, crossover study. Half way through, the placebo group will start to take the drug and vice versa. Only at the end will the data be collected and the code revealed. Understandably, many people with life-threatening or severe disorders have concerns about how soon a treatment would become widely available. The timescales for trials are very variable. For example, if the new treatment was an antibiotic for a urinary tract infection, a positive result would be apparent in each patient within a few days as the infection was eradicated, so each phase of the trials would be relatively short-term. However, for slowly progressive disorders such as muscular dystrophy the trial may last for more than a year in each patient and involve long-term follow up to ensure that any effects are of lasting value. As we have seen already from the myoblast transfer case, it is not necessarily beneficial to participate in trials, and speeding up a trial programme as happened with AZT for treating AIDs to make the treatment widely available, can have long-term drawbacks. The authorities do take into account the severity of the condition, however, when sanctioning trials and treatment licences. They recognise that the more severe a condition is, the more urgently awaited the treatment, and the more acceptable any side-effects. Chemotherapy for cancer has considerable side-effects but the therapy is common practice in view of the severity of the condition. Similar considerations would be upheld for the severe forms of muscular dystrophy and allied conditions.