Prof. Annemieke Aartsma-Rus is taking on a challenge by reading and commenting on a paper a day. She shares her insights, findings and thoughts via her @oligogirl Twitter account. See below the overview of April 2022.
Prof. Aartsma-Rus reads and comments on the paper titled: Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy
Today’s pick is the FOR-DMD trial publication on the comparison of 3 corticosteroids regimens in Duchenne published in JAMA by Guglieri et al. Doi 10.1001/jama.2022.4315
Corticosteroids improve muscle strength and function in Duchenne patients and slow down disease progression on many different levels (respiratory function, heart, walking etc). Thus, corticosteroid use is part of the standards of care for the management of Duchenne.
What is not clear is which steroids regimen is optimal (if any) & whether there is a difference between deflazacort and prednisone. To clarify things the FOR-DMD trial compared the 3 most used steroid regimen: daily prednisone, daily deflazacort, 10 days on/10 days off prednisone.
Prednisone dose: 0.75 mg/kg and deflazacort dose 0.9 mg/kg. The trial was supposed to recruit 300 patients with 100 in each regimen. Due to recruitment delays (due to also many other ongoing trials), 196 patients were included.
All patients received steroids – no placebo group. The trial took place in 32 clinical sites in 5 different countries. Patients were followed up for at least 3 years to assess functional effects, parent satisfaction and side effects.
196 patients started the trial & 164 completed it. Most of the patients who did not complete it participated in therapeutic intervention trials. In the end 55 patients completed the daily prednisone, 52 the daily deflazacort & 57 the intermittent prednisone treatment for 3 years.
Due to deflazacort supply issues some patients were on daily prednisone for a few weeks or in rare cases a few months. However, because for most patients this was only a few weeks it is unlikely to have influenced the outcome.
Looking at rise from floor time, daily treatment improved function more than intermittent treatment. There was no difference between deflazacort and prednisone. For forced vital capacity and satisfaction there was no difference between any of the groups.
Note that forced vital capacity deficits generally will appear later, so it is possible that differences will appear later. For other functional assessments also no difference was seen between daily prednisone & daily deflazacort, while intermittent prednisone was less effective.
For the side effects, hypertrochosis (excessive hairgrowth anywhere on the body) was more common for the daily regimen. Cataract was more common for deflazacort, but none of the cataracts required treatment. Growth was less stunted for the intermittent regimen.
For >35% of patients in each group the dose was reduced to account for side effects such as weight gain and abnormal behavior. This occurred most frequently in the daily prednisone group (49%).
So in summary, functionally daily regimen appear to be better than intermittent prednisone, while there is no difference between daily prednisone or daily deflazacort. Side effect wise there is less growth stunting with intermittent treatment than daily.
There are some limitations to the studies as the authors outline as well. Most importantly I think while beneficial effects are clear already after 3 years, for the side effects you will need longer term analysis. Vertebrae fractures are common after longer term treatment.
Whether this differs between the 3 tested regimen is not clear yet and will require longer follow up or retrospective analysis of larger groups. Furthermore there are more regimen (e.g. high weekend dosing) that were not included here.
While the trial was not perfect, at least at face value it does not seem to matter whether you take prednisone (available everywhere) or deflazacort (not available everywhere). I think that is a good thing to know.
I commend the authors for persevering during the difficulties of their trial and its analysis and publishing the results. Also very interested to hear what Dr. Jarod Wong has to say about all this.
Comments from Dr Jarod Wong
Fantastic to see this; congrats to the authors! All research is not “perfect” and even large-scaled studies can only answer 2 (to 3) research questions well-with more to answer. Impt to remember this. My thoughts below to add to Prof Annemieke Aartsma-Rus’ already great insights:
Pictures by Annemieke, used with permission.
Prof. Dr. Annemieke Aartsma-Rus is a professor of Translational Genetics at the Department of Human Genetics of the Leiden University Medical Center. Since 2013 she has a visiting professorship at the Institute of Genetic Medicine of Newcastle University (UK).
Her work currently focuses on developing antisense-mediated exon skipping as a therapy for Duchenne muscular dystrophy. In addition, in collaborative efforts she aims to bridge the gap between different stakeholders (patients, academics, regulators and industry) involved in drug development for rare diseases.
In 2013 she was elected a member of the junior section of the Dutch Royal Academy of Sciences (KNAW), which consists of what are considered the top 50 scientists in the Netherlands under 45. From 2015 to 2022, she was selected as the most influential scientist in Duchenne muscular dystrophy by Expertscape.