SAN DIEGO – Phase I results from the Clinical Antipsychotic Trial of International Effectiveness-Alzheimer's Disease (CATIE-AD) unveiled for the first time at the annual meeting of the American Association for Geriatric Psychiatry are so new that the presenting investigators emphasized that they're still trying to make sense of it all.
“The data we're presenting today are preliminary. We've barely gotten to understand them ourselves,” said Lon Schneider, M.D., professor of psychiatry, neurology, and gerontology at the University of Southern California, Los Angeles, who is one of the study's lead investigators. “We first saw them Feb. 4. The data should be considered preliminary until the full report is evaluated by peer review for scientific validity and clinical importance. I hope you'll keep that in mind.”
The main goal of the trial is to compare the efficacy and effectiveness of risperidone, olanzapine, and quetiapine, and examine treatment algorithms over the course of 36 weeks in treating psychosis and severe agitation in community-dwelling patients with Alzheimer's disease. The trial design has been previously described in medical literature (Am. J. Geriatr. Psychiatry 2001;9:346–60).
“This is not your pharmaceutical company's clinical trial,” Dr. Schneider remarked. “This is not a simple randomization of drug or placebo and 10 weeks later declare victory for one or another. It's also not FDA's idea of an efficacy trial. The FDA needs trials from which they can generate labeling about a drug's use. We're trying to generate information to inform clinicians on the subtleties of using medication.”
Investigators enrolled 421 Alzheimer's disease patients with a median age of 78 years in the trial from 10 private clinic sites, 25 university sites, and 2 Veterans Affairs sites nationwide, reported Pierre Tariot, M.D., the study's other lead investigator. More than half (56%) were female, 79% were white, and 18% were African American. About one-quarter did not complete high school and 34% had a high school education or GED.
Nearly 60% were married or had been married at some point, 73% lived in their own homes, 16% lived in the home of a family member, and about 10% lived in an assisted living facility.
The patients' average Mini-Mental State Exam score was 15 and the Brief Psychiatric Rating Scale (BPRS) for conceptual disorganization, suspiciousness, or hallucinatory behavior showed moderately severe psychopathology with a fairly wide range.
In terms of functional independence, about three-quarters were receiving care equivalent to nursing home care.
The trial consisted of three phases. In phase I, all 421 patients were randomized to receive one of the three atypical antipsychotics or placebo.
“At any time if a patient was not responding, they could continue the medication, increase the dose, or order a switch to a new medication,” Dr. Schneider explained. “That was done in double-blind fashion to a medication not used previously.”
Of the 421 patients, only 77 remained in phase I.
Of the remaining 344 patients, 253 moved to phase II, which started when the patient was randomized in a double-blind fashion to a second medication. If the second medication was continued, the patients remained in this phase.
“At any time if a physician, patient, or caregiver thought it was in the best interest of the patient, the patient could be pulled out into a open choice phase of the trial where the physician would treat as he might in the community,” Dr. Schneider said.
By week 4 of the trial, about one-quarter of patients discontinued their medication in phase I for “all-cause” reasons such as inadequate treatment response, study drug not sufficiently optimal, symptoms worse, unacceptable side effects, study drug no longer needed, patient or caregiver decision, or death.
By week 8, almost half of study participants had discontinued their phase I medication, and by week 12, almost three-quarters had discontinued phase I. “People were leaving the initial phase very rapidly, [but] we have not done analysis of these data adjusted for dose or length of drug exposure,” said Dr. Tariot, professor of psychiatry, medicine, neurology, and aging and developmental biology at the University of Rochester (N.Y.).
“That's critical in understanding the full meaning of these data. It's probably premature to say this, but what I'm thinking about in my own practice is whether I should treat longer with the first agent I start on,” Dr. Tariot said at the meeting. “How long do we need to treat somebody to see an effect?”
Dr. Schneider noted that there are “multiple reasons” why a study investigator could have discontinued treatment in phase I. “One main reason is that they were not being required to keep the patient in the study for 10 weeks,” he said.