WASHINGTON — Daily treatment with a combined formulation of dextromethorphan and quinidine led to a significant and clinically meaningful decrease in agitation episodes among patients with Alzheimer's disease in a controlled, phase II, 10-week study with 159 patients.
The combined, oral formulation was generally well tolerated, without appearing to cause somnolence or cognitive decline, Jeffrey L. Cummings, MD, ScD, reported at the Alzheimer's Association International Conference 2015.
A treatment that cuts the frequency and severity of agitation in Alzheimer's disease patients would be very helpful as this is “one of the most difficult symptoms for patients. [Agitation] makes it very difficult to care for a family member with Alzheimer's disease,” said Dr. Cummings, professor of neurology at the Cleveland Clinic and director of the clinic's Lou Ruvo Center for Brain Health in Las Vegas.
“Agitation is one of the most disturbing and disabling symptoms associated with Alzheimer's disease,” commented Mary Sano, PhD, professor of psychiatry and director of Alzheimer's disease research at Mount Sinai Hospital in New York. “Movement on treating this symptom has the potential to make a real difference for Alzheimer's disease patients and their caregivers,” she said.
Approved for PBA
The formulation of dextrometh-orphan and quinidine used in the study already has Food and Drug Administration marketing approval with the brand name Nuedexta for treating pseudobulbar affect (PBA), which can occur in patients with, for example, amyotrophic lateral sclerosis or multiple sclerosis. In addition, the primary active ingredient in the combination, dextromethorphan, appears in many over-the-counter formulations of cough syrup that are labeled to deliver roughly similar dosages of the drug as those used to treat PBA and tested in the current trial to treat agitation. But the OTC formulations of dextromethorphan do not include quinidine, which inhibits dextromethorphan's metabolism and results in a roughly 20-fold increase in the bioavailability of the active agent, Dr. Cummings explained.
‘Movement on treating this symptom has the potential to make a real difference for Alzheimer's disease patients and their caregivers.’
“With quinidine, we can use smaller dosages of dextromethorphan” than might be required if the drug were used by itself and thereby avoid the lethargy that could occur in patients who might require larger dosages of dextrometh-orphan without quinidine, he said in an interview.
The results he reported came from a study run at 44 U.S. centers that enrolled patients 50 to 90 years old with probable Alzheimer's disease and “meaningful” agitation secondary to their condition, who scored at least 4 on a Clinical Global Impression-Severity Scale for Agitation. The researchers excluded patients who had any other cause for their agitation. Enrolled patients averaged age 78 years, somewhat more than half were women, and they had an average score on the Mini Mental State Examination of about 17. The enrolled patients “looked like the population that you treat for agitation” secondary to Alzheimer's disease, Dr. Cummings said.
The 93 patients randomized to the investigational treatment started on 20 mg dextromethorphan and 10 mg quinidine administered orally once daily for a week, followed by an up-titration schedule over 2 weeks to reach 30 mg dextromethorphan twice daily plus 10 mg quinidine twice daily, the dosage they continued for an additional 7 weeks. The study design allowed patients to also continue on stable, preexisting regimens of memantine, cholinesterase inhibitors, and psychotropic medications.
After 10 weeks, the 93 patients on dextromethorphan plus quinidine had their average neuropsychiatric inventory domain score for agitation and aggression cut roughly in half — compared with baseline — compared with about a 25% drop in average score among 66 control patients, a statistically significant difference for the study's primary endpoint, Dr. Cummings reported. The results also showed statistically significant declines in the active-treatment vs. control arm in certain secondary efficacy measures, including patient-reported quality of life and caregiver-reported strain.
The active treatment also appeared generally well tolerated, compared with placebo. The most noteworthy safety finding was an increased rate of falls among patients on dextromethorphan plus quinidine, a 9% rate, compared with a 4% rate in the controls, a signal for this adverse effect not previously seen in other studies of dextromethorphan plus quinidine. “We were surprised with the increased falls,” Dr. Cummings said. By chance, patients randomized to the active-treatment arm had an increased history of falls, compared with patients enrolled in the control arm, which may explain the safety finding, he noted. “We will monitor falls very closely in our follow-up studies,” he said.
Effective for Dementia
A separate report at the meeting presented a new analysis of data from an open-label study that examined the same dextromethorphan plus quinidine formulation to treat 134 patients for 12 weeks with PBA secondary to dementia, stroke, or traumatic brain injury. The overall results showed that the combined formulation effectively reduced PBA in all enrolled patients, including those with dementia, a subset that predominantly included Alzheimer's disease patients. The results also showed a modest 2% rate of falls, said Rachelle S. Doody, MD, PhD, a professor of neurology and director of the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine in Houston. The new findings she reported at the meeting showed that the combined drug formulation worked equally effectively in the subset of patients with dementia, regardless of whether or not they concurrently received treatment with an antidepressant.
Clinicians should avoid using the formulation to treat agitation in Alzheimer's disease patients until data become available from phase III studies that involve at least 6 months of chronic therapy.
Despite availability of the dextromethorphan plus quinidine formulation, clinicians should avoid using it to treat agitation in Alzheimer's disease patients until data become available from phase III studies that involve at least 6 months of chronic therapy, Dr. Cummings said. “We don't want to encourage off-label use of the combined formulation until we understand it better when treating agitation in Alzheimer's disease,” he cautioned.
He also highlighted the difficulty in enrolling Alzheimer's disease patients with agitation as a significant symptom into trials, which means that completing a phase III trial could take perhaps as long as 2 more years and that FDA approval of this indication could be as long as 3 years off.
The study was sponsored by Avanir, the company that markets Nuedexta. Dr. Cummings has been a consultant to and has received honoraria from Avanir as well as from several other drug companies. He also owns stock or stock options in several companies developing drugs or other products aimed at Alzheimer's disease patients. Dr. Sano has been a consultant to Eisai, Eli Lilly, and Takeda. Dr. Doody has been a principal investigator for trials sponsored by Avanir and several other drug companies. She also has been a consultant to several drug companies.
Mitchel L. Zoler is with the Philadelphia bureau of Frontline Medical News.
Many clinicians have been using this product off-label for dementia-related agitation, although coverage can be a challenge and it is priced very high (over $700 a month) for those paying cash for it. It will be a welcome addition to the armamentarium if and when it is FDA approved for this indication, and certainly appears to be much safer than currently available off-label alternatives like antipsychotics. Although in my experience it's not dramatically effective, dextromethorphan/quinidine has definitely provided appreciable improvement in some of my agitated nursing home residents with dementias — probably more noticeably in those with vascular dementia and emotional lability, although that's not the indication being studied for possible FDA approval.
—Karl Steinberg, MD, CMD
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