Physicians, physical therapists, and researchers at the University of Rochester Medical Center are launching a large international study aimed at improving the care of muscular dystrophy patients worldwide.
Neurologist Robert "Berch" Griggs, M.D., is heading the study of treatments for Duchenne muscular dystrophy, the most common form of the disease that affects children. The condition, which affects boys almost exclusively, progresses rapidly. Boys' symptoms start when they are toddlers; untreated, they end up in a wheelchair before they become teenagers. With today's best treatments, the disease, which affects about 28,000 boys and young men in the United States, is often fatal by the time a patient reaches his 20s or early 30s.
Despite decades of research, Griggs calls the current treatment landscape for the disease "chaotic." Recently he has identified 29 different treatment regimens in use by doctors around the world.
The central feature of Duchenne muscular dystrophy is muscle weakness. The first symptoms, often seen around age 2 or 3, usually come when a boy has difficulty running, jumping, or climbing stairs. From there, even with treatment, the disease progresses very quickly. Boys are often confined to a wheelchair by age 9 or 10 because of weakness in their legs; their breathing muscles begin to fail and their heart muscle weakens dramatically in their teen years. Most patients begin receiving assisted breathing with a ventilator while they are teenagers.
About two-thirds of cases occur in families with a history of the disease - the genetic flaw responsible is passed from mother to son - but about one-third of cases occur spontaneously. That's because the disease's roots lie in a genetic flaw in the massive gene responsible for making a protein known as dystrophin, which helps make and keep muscles strong and stable. Weighing in at 2 million chemical bases, the gene is the biggest in the human body, and mutations are relatively frequent. In patients with a mutation, the body does not make enough dystrophin, and muscle fibers are gradually replaced with fat and other tissue.
In a study more than 20 years ago, in studies supported by the Muscular Dystrophy Association, Griggs and colleagues found that a daily dose of prednisone improves patients' lives dramatically. Yet Griggs has found that the treatment for Duchenne muscular dystrophy is chaotic because of concern about side effects. In a recent survey of more than 100 centers worldwide that specialize in treatment of the disease, only three were consistently using the recommended treatment - a daily dose of prednisone. Others were using prednisone intermittently or were using deflazacort; 10 weren't using steroids at all.
In the new study, patients will be randomly assigned to receive one of three steroid treatments: a) prednisone every day; b) prednisone every day for 10 days, alternating with 10-day periods without the drug; c) daily use of a steroid known as deflazacort, which is approved for use in Europe but not the United States. Neither the patients nor the researchers will be aware of the patients' treatment assignments until the conclusion of the trial.
Doctors have found that daily prednisone boosts muscle strength dramatically and that the effects are felt by patients and witnessed by parents within just 10 days. The drug boosts muscle mass by 20 percent and slows the degeneration of the muscles in patients with the disease. But concerns over side effects leave many doctors leery of prescribing the medication on a daily basis. Side effects can include weight gain, behavioral effects such as hyperactivity or irritability, and eventually loss of bone and even possibly fractures.
"People have worried about side effects of daily prednisone, and many people have felt there must be a better alternative," said Griggs, who is professor of Neurology, Medicine, Pediatrics, Pathology and Laboratory Medicine, and a member of the Center for Human Experimental Therapeutics. "Our study is designed to address exactly this question: What is the best balance between effective treatment and side effects?"
Children will be evaluated every six months for three to five years. Researchers will measure the breathing capacity of the patients, which is often an indicator of how long a patient will live; they will ask patients and parents how satisfied they are with the treatment; and they will measure how long it takes patients to stand up after lying down, which is an indicator of how long a patient will be able to walk.
"With a healthy child, if you clap your hands and tell him to stand up as quickly as he can, he's up on his feet in less than a second. With a child with Duchenne muscular dystrophy, it might take 30 times longer," said Griggs. "The child will roll onto his stomach, laboriously lift his bottom into the air, and slowly move his arms to one knee, then the other, bracing himself until he finally straightens up."
The study brings together two worldwide groups of physicians who specialize in the study of muscle disorders. The Muscle Study Group, with nearly three dozen sites in the United States, Canada, and Europe, is based in Rochester and headed by Griggs. The TREAT-NMD study group is a consortium of dozens of institutions across Europe and elsewhere that work together to study neuromuscular disorders. TREAT-NMD is headed by Bushby, who is Action Research Professor of Neuromuscular Genetics at Newcastle University in the United Kingdom.
Bushby and Griggs are leading the clinical aspects of the new study. Michael McDermott, Ph.D., professor of Biostatistics and Neurology, and Rabi Tawil, M.D., professor of Neurology, are co-leaders of biostatistical analysis and data management.
The team from Rochester also includes Barbara Herr, assistant professor of Neurology, manager of the U.S. portion of the project; associate project manager Christine Annis; Shree Pandya, lead U.S. physical therapist; Mary Brown, Heart Research Program manager; William Martens, data manager; and Emma Ciafaloni, M.D., associate professor of Neurology, who will lead the study of patients in Rochester.
Griggs is central to the international effort to find an effective treatment for the disease. Last week, for readers of the journal Lancet Neurology, Griggs was asked to put into perspective new findings from a study of the drug cyclosporine, which recently proved safe but not effective for patients. Griggs also served as the head of the data and safety monitoring board for a study of an investigational drug called ataluren conducted by PTC Therapeutics; earlier this year the company announced that the drug, though safe, failed to help patients in the ways doctors had hoped. Analysis of those data continues.