Instead of doing poorly, patients using the faulty device actually experienced better outcomes than did those who entered the study later and used a more reliable inhaler,said at the Clinical Trials on Alzheimer’s Disease conference.
A secondary analysis of thesubgroup “replicated findings in our original studies,” which used the same atomizer, said Dr. Craft, a professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C. “We remain optimistic, but clearly we are at the beginning of understanding optimal insulin doses and delivery techniques for this population.”
The 289-patient, placebo-controlled study was predicated by a prior successful study by Dr. Craft and her colleagues, published in 2012 in. That trial randomized 104 patients with amnestic mild cognitive impairment (MCI) or mild-moderate Alzheimer’s to placebo or intranasal insulin 20 or 40 IU. After 4 months, subjects in both insulin groups showed preserved cognition and functional abilities, as well as increased cerebral glucose metabolism.
The ViaNase device was manufactured by Kurve Technology. But the company redesigned it for the new trial, adding an electronic timing component, which Dr. Craft said, was supposed to increase ease of use.
“Unfortunately, there were frequent malfunctions of this mechanism for the first 49 patients – so much so that we had to discontinue using the device and switch to a newer one,” for the other 240 patients in the study. This intranasal drug-delivery system, called the Precisions Olfactory Delivery ( ) device, is made by Impel NeuroPharma. Dr. Craft’s trial is its first investigation in patients with Alzheimer’s disease.
The new study randomized 289 patients with MCI or mild Alzheimer’s to twice-daily sprays with a placebo device, or to intranasal insulin 40 IU for 12 months, followed by a 6-month, open-label period. The primary outcome was the Alzheimer’s Disease Assessment Scale-Cognition measure (). Secondary outcomes were the Clinical Dementia Rating Scale sum of boxes ( ) a memory composite measure, activities of daily living, cerebrospinal fluid biomarkers, and MRI of the hippocampus and entorhinal cortex.
Because of the device problems, Dr. Craft conducted separate analyses for the user groups. The primary was an intent-to-treat (ITT), mixed-model, repeat-measures analysis of the 240 using the POD device. The model controlled for age, sex, genetic risk status, and investigation site. An exploratory ITT analysis looked only at the ADAS-Cog 12 in the 49 who used the ViaNase device. Patients were a mean of 71 years old, with a mean Mini Mental State Exam score of 25. About 42% were positive for the high-risk apolipoprotein E epsilon-4 allele.
At 12 months, there was no between-group difference on the ADAS-Cog 12 measure; both groups increased by about 4 points, indicating worsening. Nor were there any changes in any of the Alzheimer’s-related biomarkers: amyloid-beta 40 and 42, total tau, or phosphorylated tau. There was a small but statistically significant difference in the sizes of the hippocampus and entorhinal cortex.
The ViaNase group fared somewhat better in the secondary analysis of the ADAS-Cog12. The measure increased by about 5 points in the placebo group, and about 2.5 points in the insulin group. The significant separation was evident at 3 months and continued to widen over the course of the study.
Compliance was very good in the larger group – around 85%. It was lower in the ViaNase group, probably because of the device’s unreliability. Retention was good in both groups. There were no significant differences in adverse events and no obvious safety issues.
The 6-month, open-label period will close out before the end of the year. In the meantime, Dr. Craft is conducting additional subgroup analyses on the 12-month data.
Dr. Craft has served as a consultant for GlaxoSmithKline and Accera.
SOURCE: Craft S et al. J Prev Alz Dis 2018;5(S1):S9,