Clinical Trials and Studies November-December 2008

Article Highlights:

Updates on the latest clinical trials and studies as of October 2008

by Quest Staff on November 1, 2008 - 7:07am

QUEST Vol. 15, No. 6

This story includes items about: Becker, Duchenne and limb-girdle muscular dystrophies; myasthenia gravis; carnitine palmityl transferase 2 deficiency; inclusion-body myopathy

Gene transfer trial under way in LGMD2D

A small, MDA-supported study to test the safety of injecting alpha-sarcoglycan genes into a leg muscle in children and adults with type 2D limb-girdle muscular dystrophy (LGMD2D)is under way at Nationwide Children’s Hospital in Columbus, Ohio. LGMD2D results from a lack of the muscle protein alpha-sarcoglycan. (See “Gene transfer in LGMD2D mice bodes well for human trial.”) Participants must be at least 5 years old and meet other criteria. Contact Xiomara Rosales-Quintero at (614) 722-6961 or

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CellCept disappointing in two myasthenia gravis trials

Two large trials of the potent immunosuppressant myocophenolate mofetil (CellCept) in the autoimmune disease myasthenia gravis (MG) have, surprisingly, yielded results that suggest the drug is no better than standard treatment with the corticosteroid prednisone in treating this disease. The findings from both studies were published in the Aug. 5 issue of Neurology.

Both trials were double-blind, meaning neither participants nor investigators knew which substance was being taken; and randomized, meaning each participant had an equal chance of being assigned to receive the study drug or a placebo (inactive substance).

The first, a 13-center, U.S.-based study of 80 people with MG, compared 2.5 grams per day of mycophenolate mofetil plus 20 milligrams a day of prednisone, to a placebo plus 20 milligrams a day of prednisone, over three months.

The investigators, coordinated by Donald Sanders at Duke University, were members of the Muscle Study Group, which includes several MDA clinic directors. They measured changes in muscle strength and function between the start and end of the study, using the “quantitative myasthenia gravis” standardized scale.

The average change in score on the MG scale was similar in the prednisoneplus mycophenolate and the prednisoneplus-placebo groups.

The second study, an international trial that included 88 participants from 43 centers in several countries, included patients with MG who had been taking prednisone for at least four weeks. Donald Sanders coordinated the publication group.

For nine months, participants were randomly assigned to additional treatment with either 2 grams per day of mycophenolate mofetil or a placebo, while their prednisone dosage was gradually reduced on a predetermined schedule.

They were evaluated on the quantitative MG scale, as well as on scales of activities of daily living and a general health survey.

Mycophenolate mofetil wasn’t any better than a placebo at maintaining MG control during the nine months of prednisone dose reduction.

In the same issue of Neurology, Michael Benatar, co-director of the MDA clinic at Emory University in Atlanta and an MDA research grantee, and Lewis Rowland, former director of the MDA/ALS Center at Columbia University in New York and a former MDA research grantee, probed some of the explanations the investigators offered as an alternative to concluding that mycophenolate mofetil simply isn’t any more effective than prednisone in MG.

They note that the MG studies may have been too short to show an effect of mycophenolate; that prednisone may have been more effective than expected in these study participants, leading to an obliteration of any difference between the groups treated with mycophenolate and those treated with prednisone alone; that, in one or both studies, the criteria used to judge change may have been so stringent that small changes that patients might consider significant were overlooked; and/or that the patients in these trials may not represent the general MG population.

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Special diet and supplement relieve symptoms in seven with CPT2 deficiency

Seven people with carnitine palmityl transferase 2 deficiency (CPT2) who took a special dietary supplement and followed a prescribed diet for seven months to five years found their exerciseassociated muscle pain, as well as dangerous episodes of acute muscle breakdown, resolved.

Without the CPT2 enzyme, compounds called long-chain fatty acids can’t enter cellular structures known as mitochondria, where they normally would be utilized for energy production.

The energy deficit experienced by people with CPT2 deficiency makes exercise difficult or impossible and can cause frequent episodes of rapid muscle destruction that leads to kidney damage. A low-fat, high-carbohydrate diet is a standard therapy, but it’s only moderately effective.

Charles Roe at the Institute of Metabolic Disease at Baylor University Medical Center in Dallas, and colleagues, who published their results in the July 22 issue of Neurology, gave study participants a compound called triheptanoin as a substitute for most dietary fat in a special diet.

Triheptanoin is a molecule containing three medium-chain fatty acids (heptanoate) attached to a carbohydrate (glycerol) backbone. Unlike long-chain fatty acids, which require CPT2 or other enzymes to enter mitochondria, heptanoate can enter these structures by itself.

The study participants, who ranged in age from 10 to 55, ate a diet that was 13 percent protein, 37 percent carbohydrates and 20 percent fat, with triheptanoin oil making up the remaining 30 percent of daily calories. They mixed the oil in foods such as yogurt or pudding and ingested it slowly at each meal and at bedtime, as well as 30 minutes before strenuous activity.

Participants who adhered to the triheptanoin diet avoided hospitalization and muscle breakdown, and only two experienced even mild muscle pain with exercise. All seven reported they could perform strenuous activities, including team sports, swimming, aerobics, skiing and hiking.

Triheptanoin oil is not available except in research studies. However, it has been granted “orphan product status,” which fast-tracks development of drugs for rare diseases, by the U.S. Food and Drug Administration.

Roe and colleagues are collaborating with corporations to develop a powder form of triheptanoin that can be taken orally or dissolved for use as an intravenous therapy.

People with CPT2 deficiency should consult their physicians before taking a dietary supplement or starting a special diet.

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Cardiomyopathy with DMD, with BMD, and without MD follow different courses

Cardiac muscle deterioration (cardiomyopathy) tends to follow a different course in children with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), and both courses are different from the progression of cardiomyopathy from other causes, according to a report published in the June issue of the American Heart Journal.

Data for the report were gathered from 57 pediatric cardiac centers by the Pediatric Cardiomyopathy Registry, a database sponsored by the National Institutes of Health in Bethesda, Md. MDA helped support the study.

Steven Lipshultz at the University of Miami Miller School of Medicine coordinated the study team, which analyzed medical records of patients with a diagnosis of cardiomyopathy who visited a pediatric cardiologist between 1990 and 2005.

Fifteen children and adolescents with BMD-associated cardiomyopathy, 128 with DMD-associated cardiomyopathy, and 312 with cardiomyopathy from other causes were included. All were 18 or younger when their cardiac condition was diagnosed.

Patients with BMD were less likely to experience marked cardiomyopathy as children, but when they did, they generally had more severe symptoms than those with DMD, the investigators say.

They found there may be two separate groups of children with BMD, one with very rapid cardiac deterioration and one with more stable function. The authors recommend cardiac evaluations for BMD patients in their childhood and mid-teen years and, if indicated, early treatment.

At the time of diagnosis, children with DMD and BMD had better function of the left ventricle (lower left pumping chamber) of the heart on some measures than did children with other types of cardiomyopathies, but the walls of their left ventricles were thinner and smaller.

Children with MD, the investigators note, have ongoing loss of cardiac muscle cells, which is less likely to occur in children with cardiomyopathy from other causes. The MD-affected children generally had a more severe cardiomyopathy disease course than the non-MD-affected children, which the investigators say may be related to this cell loss.

Children with cardiomyopathies without DMD or BMD, however, had a higher incidence of a condition known as congestive heart failure at the time of diagnosis than those with MD.

Children with DMD had a shorter survival time after diagnosis of cardiomyopathy than did children with either BMD or no MD, which the authors say may result in part from their lack of access to heart transplantation compared to the other groups.

“Although large studies have not been performed in these [MD] patients, many experts in this field believe that the initiation of medical treatment at or even before the first signs of cardiomyopathy may delay the appearance of heart failure symptoms,” Lipshultz said.

Until specific treatments for MD are developed, the investigators say, children with DMD- or BMD-associated cardiac dysfunction should be cared for using current guidelines, such as those developed by the American Academy of Pediatrics (see “Let the Beat Go On,” March-April 2006).

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UC Irvine professor seeks people with rare muscle and bone disorder

Virginia Kimonis, a professor of pediatrics at the University of California-Irvine, is conducting a study of people with hereditary inclusion-body myopathy (IBM) accompanied by either bone pain and susceptibility to fractures and/or by mental deterioration. The combination of these three conditions has been traced to mutations in the VCP gene. Contact Kimonis at (714) 456-5791, (949) 824-0571 or

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Parents sought for survey of genetic counseling experiences, knowledge

A graduate student in the Genetic Counseling Program at the University of Maryland School of Medicine in Baltimore is conducting a large-scale survey of what parents of children with neuromuscular disorders know about the genetic basis of their child’s condition and how this information was obtained. The investigators hope to improve parental education in this area. Contact Jacquelyn Francis at with questions or concerns.

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