Multisite clinical trial will compare three FDA-approved drugs for Rett syndrome treatment

Vanderbilt University Medical Center received a $13 million Department of Defense grant to lead a multisite clinical trial that will evaluate repurposed FDA-approved drugs as treatment options for patients with Rett syndrome.

Affecting 1 in 10,000 females at birth, and males even more rarely, Rett syndrome is a rare genetic neurodevelopmental disorder that affects brain development.

“It robs affected individuals of the ability to use their hands or speak and causes problems with mobility, as well as a number of other issues,” said Jeffrey Neul, Annette Schaffer Eskind Professor, director of the Vanderbilt Kennedy Center and the grant’s principal investigator. “People with Rett syndrome require lifelong care for activities of daily living. Although symptom management, therapies and a newly FDA-approved drug can help, there remains a great need to find new therapies to improve the lives of people with Rett syndrome.”

The study is an umbrella trial that will compare three FDA-approved drugs, ketamine, vorinostat and donepezil, to a common placebo. Participants will be randomized equally to one of the four treatment arms for a 16-week treatment to assess safety, tolerability, efficacy and biomarker response.

“The study will evaluate FDA-approved drugs that have preclinical evidence supporting potential clinical benefit,” Neul said. “If any of these drugs show benefit in this trial, further clinical evaluation and ultimately use treating people with Rett syndrome could progress rapidly. Additionally, successful establishment of this clinical trial platform will allow accelerated evaluation of other potential therapies in Rett syndrome.”

Participants will be recruited from four trial sites, including VUMC, Children’s Hospital of Philadelphia, Boston Children’s Hospital and Children’s Hospital of Colorado, all International Rett Syndrome Foundation (IRSF)-designated Rett Syndrome Centers of Excellence. Coordination of the trial will be led by VUMC, which has led a number of industry-sponsored and investigator-initiated clinical trials for Rett syndrome, including the recent successful phase 3 trial that led to the first FDA-approved drug for this condition.

“Vanderbilt has a long history of providing best-in-class care to Rett syndrome patients as one of only 18 Rett clinics across the country that IRSF designated as a Center of Excellence,” said Melissa Kennedy, chief executive officer of IRSF. “Dr. Neul and the Vanderbilt team have proven themselves as research leaders as well, conducting clinical research and coordinating trials that have not only expanded our understanding of the fundamental science behind Rett syndrome but also played a pivotal role in delivering the first-ever FDA-approved treatment.”

According to Kennedy, more approved treatments for individuals with Rett means they can “do more and suffer less” as soon as possible.

“Rett is such a complex disorder that no one treatment is going to be right for every individual. We need multiple options to have an impact on every individual with Rett syndrome. By testing compounds that are already FDA-approved and show promise for application in Rett patients, this study can help get treatments into the hands of families much sooner than a compound just entering the pipeline,” she said.

According to Neul, the drugs being tested in this study may uncover benefits for other neurological and mental health disorders. This includes building the safety profile of ketamine in the pediatric population, which is being studied separately for the treatment of depression, post-traumatic stress disorder and other conditions in adults.