The U.S. Department of Defense has awarded $13 million to Vanderbilt University Medical Center for a clinical trial of three drugs being repurposed to treat children with Rett Syndrome.
The drugs – ketamine, vorinostat and donepezil – are already approved for a variety of conditions, including donepezil for symptoms of dementia.
The trial design involves a master protocol, an approach with flexibility and frugality built in, said principal investigator Jeffrey Neul, M.D., Ph.D., Annette Schaffer Eskind Chair of Pediatric Neurology, director of the Vanderbilt Kennedy Center and a professor at Vanderbilt University Medical Center.
“Using this master protocol means that we’re starting by comparing all three of these drugs against a common placebo,” Neul said, adding that each study arm will include 25 participants. In contrast, most trials create a separate control group for each drug tested.
“We’re gaining an advantage by sharing placebo information instead of running three trials with the same number of people on each drug with a total of 75 people taking a placebo,” he said.
Maximizing Resources
Having a common placebo group is particularly advantageous in testing drugs for rare disorders such as Rett Syndrome, where finding participants for clinical trials can be difficult. The protocol also allows for flexibility, using rules that can be customized.
“You might do an interim analysis and decide that carrying on with one of the drugs is futile. You see there’s no benefit midway, so you drop that arm,” Neul said.
“Our big goal is not just to test these three initial drugs. We envision that we’ve set up a platform that can be kept running even after Department of Defense funds run out.”
At the same time, another drug may be showing promising preclinical evidence and that drug can be added as a new arm in the ongoing trial.
“Our big goal is not just to test these three initial drugs,” Neul said. “We envision that we’ve set up a platform that can be kept running even after Department of Defense funds run out.”
Other researchers will be able to use the master protocol to test other FDA-approved drugs, meaning more candidates can be appraised in a cost-effective, streamlined manner.
Matters of Defense
The Department of Defense funds Congressionally Directed Medical Research Programs, many of which address medical problems faced by active members of the military and veterans.
“A drug that could help people who have lost skills due to a genetic disorder might also be beneficial for a person who lost an ability for other reasons, such as a traumatic brain injury,” Neul explained.
Patients Lose Progress
A rare neurological disorder, Rett syndrome affects brain development, motor skills, speech and other abilities. It mostly affects female children.
The condition becomes evident after apparently normal development between birth and about six months, when the rate of learning slows down in a child with Rett syndrome. Between 18 and 30 months, their skills start to regress.
“They specifically lose acquired language skills and acquired hand skills and develop a characteristic repetitive hand movement. When you lose a skill you had already gained, it’s dramatic,” Neul said.
In almost all cases, Rett syndrome occurs as a result of a spontaneous genetic mutation in the methyl-CpG-binding protein 2 (MECP2) gene. Very rarely, Rett mutations can be inherited by female carriers and passed on to their children.
Hope for New Treatment
“For a long time, there was a sentiment among drug companies that certain neurodevelopmental disorders, like Rett Syndrome, were intractable and that you couldn’t develop drugs that the FDA would approve,” Neul said.
“Now we know that it is possible to get an approved drug. That is very hopeful for the development of drugs in Rett Syndrome and other neurological disorders.”
Concern was so widespread across the field, he added, that funding to search for treatments was exceedingly hard to come by.
Then, a year ago, the FDA issued its first approval of a drug for Rett Syndrome, trofinetide. That fostered hope that treatments might be found for other rare neurodevelopmental disorders as well.
“Now we know that it is possible to get an approved drug. That is very hopeful for the development of drugs in Rett Syndrome and other neurological disorders.”
