Because of the global COVID-19 pandemic, Italfarmaco has paused enrollment of boys with Duchenne muscular dystrophy (DMD) in a Phase 3 trial of its investigational treatment givinostat, the company said in a recent webinar hosted by Parent Project Muscular Dystrophy.
Although treatment of current participants remains on schedule, this is expected to delay trial completion and submissions seeking regulatory approval of givinostat.
“The clinical trials [of givinostat] are all ongoing, so we did not have any stop in the study,” said Paolo Bettica, MD, PhD, chief medical officer at Italfarmaco. “However, the enrollment — so, the screening and randomization part — is currently paused, because of the travel restrictions, because of the restrictions on the sites, and also because most of our MRI sites at the moment are not allowing kids to be measured.”
Givinostat, given as a liquid suspension, works by blocking the activity of histone deacetylases (HDACs) — enzymes that control gene activity by changing how tightly coiled DNA is in the nucleus of a cell. Studies have suggested that HDACs are over-active in DMD and related conditions, which may contribute to muscle degeneration.
Givinostat’s potential in DMD is supported by data from a Phase 2 trial (NCT01761292), in which boys with DMD (ages 7–11) were treated with givinostat or a placebo for a year, along with a stable dose of corticosteroids. Results showed that the therapy significantly increased the amount of muscle, as assessed by muscle biopsies, decreased tissue death, and lessened fibrosis (scarring). Treatment with givinostat also reduced deterioration in lung function and delayed the median age at which boys lost the ability to walk.
In the current Phase 3 trial (NCT02851797), treatment with givinostat is being studied in boys, ages 6–17, who are able to walk, are on stable treatment with corticosteroids for at least six months, and are able to climb four steps in up to eight seconds, among other criteria.
The study’s main goal is to determine givinostat’s ability to slow disease progression, as measured by the change in the time to climb four stairs after 18 months of treatment. Other functional tests, as well as muscle imaging, are also being conducted. Givinostat (10 mg/mL) is being compared to a placebo, both given twice daily with food.
A futility analysis for the study was conducted last February. This type of assessment evaluates whether it is mathematically possible for a trial to achieve its goal — if not, it is common to stop the trial to save resources and minimize participant burden. The Phase 3 trial of givinostat passed this analysis, supporting its continuation.
At the same time, an analysis was conducted to re-evaluate the number of participants necessary for the study. The original design planned to enroll 213 participants, but new estimations support reducing the number of participants to 169 boys. Notably, 160 boys had already been enrolled when recruitment was stopped.
The trial was originally planned to finish enrollment this June, and to be concluded in March 2022.
“I believe that, because of COVID[-19] and because of where we are, it’s going to be extended beyond June, but hopefully it’s going to be just a couple of months,” Bettica said. “We should have some delay, but hopefully it’s very small.”
The study is being conducted at multiple sites in North America, Israel, and Europe. More information is available here.
In addition to delayed enrollment, modifications to the study procedure are being put in place to protect current participants. Broadly, these steps are intended to minimize the need for participants to go to trial sites. Some procedures that would normally be done at hospitals, such as blood draws, are being done by nurses at the boys’ homes. A system has also been put in place to ship givinostat directly to participants’ homes if needed.
Similar procedures have been adopted in an ongoing Phase 2 trial (NCT03238235) of one-year givinostat treatment in men with Becker muscular dystrophy. This trial, conducted in Italy and the Netherlands, completed enrollment in February. Safety analyses will be conducted along with measurements of muscle and motor function.
All those with DMD who took part in clinical trials of givinostat can join a long-term Phase 2/3 trial (NCT03373968), in which the therapy’s safety, tolerability, and efficacy will be further assessed. This study will be conducted in North America and Europe. More information is available here.
People with chronic neuromuscular disorders and other chronic conditions, such as muscular dystrophy, may be at a greater risk for more severe symptoms if they become infected with COVID-19. But, according to Bettica, such risk is not increased by taking givinostat.
“There is no data suggesting an interaction of givinostat with COVID[-19],” he said.
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