麻豆传媒

SEATTLE -- Prednisone or deflazacort given every day were superior to prednisone on a 1o-days-on, 10-days-off schedule for boys with Duchenne muscular dystrophy (DMD), a researcher reported.

In the international trial, both daily regimens led to "significant improvement over 3 years" in scores summarizing motor function, respiratory health, and treatment satisfaction, reported Michela Guglieri, MD, of Newcastle University in England, at the American Academy of Neurology annual meeting held in Seattle and online. Findings also were published simultaneously in .

Although newer agents are now approved for DMD, corticosteroids remain the foundation of therapy. Many studies have confirmed that steroids boost muscle function, but dosing schedules in routine practice vary widely. Guglieri and colleagues noted that when they started planning the current trial in 2004, physician surveys found 29 different regimens in use.

Those surveys also identified three in particular as the most popular:

• Daily prednisone at 0.75 mg/kg
• Daily deflazacort at 0.90 mg/kg
• Cycles of prednisone at 0.75 mg/kg for 10 days followed by 10 days off

An international research consortium determined that a randomized trial was called for to settle which, if any, is best.

The trial actually began in 2012, eventually randomizing 196 steroid-naïve boys with DMD (mean age 5.8) to the three regimens, with outcomes tracked for 3 years. Most participants came from the U.S. and the U.K., with about one-third from Canada, Germany, and Italy. The following three measures constituted the primary outcomes:

• Speed in rising from the floor
• Forced vital capacity
• Patient or parent score on the 100-point

Secondary measures included 10-m walk or run speed, 6-minute walk distance, cardiac function, range of ankle motion, , and others.

Mean rising speed at baseline was 0.19 rises per second (originally, this measure had been set as time to rise, but this proved mathematically impractical when some participants were unable to rise at all, and thus had a rise time of infinity). Speed to walk or run 10 m averaged about 1.7 m/second, and mean forced vital capacity was 1.1 L or about 86% of predicted.

The daily regimens' advantage over the on/off prednisone cycling was concentrated in the rising-speed measure. When tested at year 3, rising speed for daily prednisone and daily deflazacort clocked in at 0.236 and 0.240 per second, respectively, whereas it reached only 0.180 for intermittent prednisone (P=0.003 vs daily prednisone and P=0.017 vs daily deflazacort). There was no material difference among regimens for either forced vital capacity, which topped 1.4 L in all groups at year 3, or treatment satisfaction score.

However, all secondary measures evaluating motor function favored the two daily regimens. For example, 10-m run/walk speed was greater by about 0.3 m/second in both daily dosing groups than with on/off prednisone (both P=0.001). Results were equivocal for other secondary outcomes.

During the study, 8% of participants lost walking ability and 14% could no longer rise from the floor.

Safety findings were as expected and did not differ markedly among regimens, except that patients on daily prednisone gained a full point of BMI more than those on intermittent dosing. Weight gain in the two groups was about the same -- about 13 kg (about 29 lbs) -- both significantly more, by some 3 kg, than in the daily deflazacort group.

Dosage reductions because of adverse events (AEs) were made for half of the daily prednisone group and about 35% of the two other study arms. The most common AEs leading to such reductions were Cushingoid appearance, weight gain, and abnormal behaviors. On the other hand, reductions were usually temporary, and in nearly 90% of cases, it reflected choices not to increase dosages according to the original weight-based formula, rather than an absolute reduction in milligrams given. At year 3, 67%-75% of participants were taking their protocol-prescribed doses.

The trial suffered other problems, too, that may detract from its conclusiveness. Guglieri and colleagues initially hoped to enroll 300 patients, but had to terminate recruitment at 196 because it was proving too slow. That left them short of the number calculated to provide 80% power to find significant differences in at least two of the three primary outcome measures. Some participants didn't complete the full 3 years of follow-up; Guglieri and colleagues had at least 30 months of data for 84% of the 196 randomized.

Also, shortages of study drugs meant that about 40% of participants had to switch to open-label daily prednisone for periods of a few weeks in most cases (though the switch lasted several months for 14 patients in Italy and Canada). And 11 participants decided to join trials of other drugs while remaining in FOR-DMD -- it's a rare condition with a limited pool of potential trial participants -- such that their data after starting these other trials had to be excluded from the current analysis.

Guglieri and colleagues noted that some aspects of specific steroid regimens' efficacy and safety may need longer than 3 years to evaluate fully. And they acknowledged that the three tested, while thought to be the most common, are not necessarily the best possible.

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