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Latest intranasal insulin results for Alzheimer’s muddied by malfunctioning inhaler
BARCELONA –
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, Suzanne Craft, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
A secondary analysis of the ViaNase device subgroup “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 JAMA Neurology. 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 (POD) 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 (ADAS-Cog 12). Secondary outcomes were the Clinical Dementia Rating Scale sum of boxes (CDR-sb) 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, Abstract OC2.
BARCELONA –
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, Suzanne Craft, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
A secondary analysis of the ViaNase device subgroup “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 JAMA Neurology. 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 (POD) 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 (ADAS-Cog 12). Secondary outcomes were the Clinical Dementia Rating Scale sum of boxes (CDR-sb) 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, Abstract OC2.
BARCELONA –
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, Suzanne Craft, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
A secondary analysis of the ViaNase device subgroup “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 JAMA Neurology. 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 (POD) 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 (ADAS-Cog 12). Secondary outcomes were the Clinical Dementia Rating Scale sum of boxes (CDR-sb) 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, Abstract OC2.
REPORTING FROM CTAD
IDEAS study meets first aim of changing 3-month clinical management, health outcomes
BARCELONA – Amyloid PET brain imaging changed clinical management in 60% of patients with a diagnosis of mild cognitive impairment or dementia and confirmed a presumptive Alzheimer’s diagnosis in 95% of those with positive scans.
But the scans also benefited amyloid-negative patients, Gil Rabinovici, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Before the test, 71% carried an Alzheimer’s disease (AD) diagnosis; after the test, just 10% did, opening the way for an accurate diagnosis and more effective treatment.
“These patients were saved from unnecessary treatment for Alzheimer’s,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. They received more suitable care plans because of the confirmation.
He presented final results of aim one of the IDEAS (Imaging Dementia–Evidence for Amyloid Scanning) study, which seeks to prove that amyloid imaging changes clinical management and improves health outcomes in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two aims are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and that this impacts major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.
Ultimately, investigators hope the U.S.-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service.
So far, IDEAS has accrued data on 11,409 patients and is quickly closing in on the 18,000-patient target. The patients reported on at CTAD were aged a mean of 75 years and were largely white; only 4% were black and 4% Hispanic. The mean Mini-Mental Scale Exam score was 26. AD was the leading suspect pathology in 73% of the 6,905 with MCI and in 83% of those with dementia of uncertain etiology. Overall, 44% were taking AD medications at baseline.
Scans were positive in 55% of those with MCI and in 70% of those with dementia. Overall, the scans changed clinical management in 61% (7,018), including 60% of those with MCI and 63% of those with dementia.
“We also asked physicians how much the scan results contributed to these changes, and 86.7% replied that they ‘contributed significantly,’ ” Dr. Rabinovici said.
Most changes involved adjustments to medication. AD drugs were started in 44% of MCI patients and in 45% of dementia patients, and non-AD drugs started in 22% and 25%, respectively. About a fifth of the patients received counseling in wake of the scan results.
Medication adjustments also varied by scan result. Among amyloid-positive MCI patients, AD drug use increased from 40% before imaging to 81% after; among amyloid-negative MCI patients, drug use decreased slightly from 27% to 24%. Among amyloid-positive dementia patients, AD drug use increased from 63% to 91%, and among amyloid-negative patients, it dropped from 50% to 44%. All these changes were statistically significant.
The primary diagnosis changed from AD to non-AD in 25%, and from non-AD to AD in 10%. Among amyloid-positive patients, the diagnosis prevalence jumped from 80.0% to 95.5%; among amyloid-negative patients, it dropped from 71% to just 10%.
“IDEAS now provides the strongest data we have supporting the beneficial impact of amyloid PET on patient management,” said Dr. Rabinovici. “Aim two, which is the 12-month health outcomes, we expect to be completed by the end of next year.”
The IDEAS team is also looking at a furthering the investigation with a study called, aptly, “NEW IDEAS.” That would reach out to recruit the minorities that were so underrepresented in the main study and include patients with early-onset MCI or dementia. Building up a library of DNA and blood plasma samples might also fit into the new project.
IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.
BARCELONA – Amyloid PET brain imaging changed clinical management in 60% of patients with a diagnosis of mild cognitive impairment or dementia and confirmed a presumptive Alzheimer’s diagnosis in 95% of those with positive scans.
But the scans also benefited amyloid-negative patients, Gil Rabinovici, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Before the test, 71% carried an Alzheimer’s disease (AD) diagnosis; after the test, just 10% did, opening the way for an accurate diagnosis and more effective treatment.
“These patients were saved from unnecessary treatment for Alzheimer’s,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. They received more suitable care plans because of the confirmation.
He presented final results of aim one of the IDEAS (Imaging Dementia–Evidence for Amyloid Scanning) study, which seeks to prove that amyloid imaging changes clinical management and improves health outcomes in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two aims are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and that this impacts major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.
Ultimately, investigators hope the U.S.-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service.
So far, IDEAS has accrued data on 11,409 patients and is quickly closing in on the 18,000-patient target. The patients reported on at CTAD were aged a mean of 75 years and were largely white; only 4% were black and 4% Hispanic. The mean Mini-Mental Scale Exam score was 26. AD was the leading suspect pathology in 73% of the 6,905 with MCI and in 83% of those with dementia of uncertain etiology. Overall, 44% were taking AD medications at baseline.
Scans were positive in 55% of those with MCI and in 70% of those with dementia. Overall, the scans changed clinical management in 61% (7,018), including 60% of those with MCI and 63% of those with dementia.
“We also asked physicians how much the scan results contributed to these changes, and 86.7% replied that they ‘contributed significantly,’ ” Dr. Rabinovici said.
Most changes involved adjustments to medication. AD drugs were started in 44% of MCI patients and in 45% of dementia patients, and non-AD drugs started in 22% and 25%, respectively. About a fifth of the patients received counseling in wake of the scan results.
Medication adjustments also varied by scan result. Among amyloid-positive MCI patients, AD drug use increased from 40% before imaging to 81% after; among amyloid-negative MCI patients, drug use decreased slightly from 27% to 24%. Among amyloid-positive dementia patients, AD drug use increased from 63% to 91%, and among amyloid-negative patients, it dropped from 50% to 44%. All these changes were statistically significant.
The primary diagnosis changed from AD to non-AD in 25%, and from non-AD to AD in 10%. Among amyloid-positive patients, the diagnosis prevalence jumped from 80.0% to 95.5%; among amyloid-negative patients, it dropped from 71% to just 10%.
“IDEAS now provides the strongest data we have supporting the beneficial impact of amyloid PET on patient management,” said Dr. Rabinovici. “Aim two, which is the 12-month health outcomes, we expect to be completed by the end of next year.”
The IDEAS team is also looking at a furthering the investigation with a study called, aptly, “NEW IDEAS.” That would reach out to recruit the minorities that were so underrepresented in the main study and include patients with early-onset MCI or dementia. Building up a library of DNA and blood plasma samples might also fit into the new project.
IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.
BARCELONA – Amyloid PET brain imaging changed clinical management in 60% of patients with a diagnosis of mild cognitive impairment or dementia and confirmed a presumptive Alzheimer’s diagnosis in 95% of those with positive scans.
But the scans also benefited amyloid-negative patients, Gil Rabinovici, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Before the test, 71% carried an Alzheimer’s disease (AD) diagnosis; after the test, just 10% did, opening the way for an accurate diagnosis and more effective treatment.
“These patients were saved from unnecessary treatment for Alzheimer’s,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. They received more suitable care plans because of the confirmation.
He presented final results of aim one of the IDEAS (Imaging Dementia–Evidence for Amyloid Scanning) study, which seeks to prove that amyloid imaging changes clinical management and improves health outcomes in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two aims are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and that this impacts major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.
Ultimately, investigators hope the U.S.-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service.
So far, IDEAS has accrued data on 11,409 patients and is quickly closing in on the 18,000-patient target. The patients reported on at CTAD were aged a mean of 75 years and were largely white; only 4% were black and 4% Hispanic. The mean Mini-Mental Scale Exam score was 26. AD was the leading suspect pathology in 73% of the 6,905 with MCI and in 83% of those with dementia of uncertain etiology. Overall, 44% were taking AD medications at baseline.
Scans were positive in 55% of those with MCI and in 70% of those with dementia. Overall, the scans changed clinical management in 61% (7,018), including 60% of those with MCI and 63% of those with dementia.
“We also asked physicians how much the scan results contributed to these changes, and 86.7% replied that they ‘contributed significantly,’ ” Dr. Rabinovici said.
Most changes involved adjustments to medication. AD drugs were started in 44% of MCI patients and in 45% of dementia patients, and non-AD drugs started in 22% and 25%, respectively. About a fifth of the patients received counseling in wake of the scan results.
Medication adjustments also varied by scan result. Among amyloid-positive MCI patients, AD drug use increased from 40% before imaging to 81% after; among amyloid-negative MCI patients, drug use decreased slightly from 27% to 24%. Among amyloid-positive dementia patients, AD drug use increased from 63% to 91%, and among amyloid-negative patients, it dropped from 50% to 44%. All these changes were statistically significant.
The primary diagnosis changed from AD to non-AD in 25%, and from non-AD to AD in 10%. Among amyloid-positive patients, the diagnosis prevalence jumped from 80.0% to 95.5%; among amyloid-negative patients, it dropped from 71% to just 10%.
“IDEAS now provides the strongest data we have supporting the beneficial impact of amyloid PET on patient management,” said Dr. Rabinovici. “Aim two, which is the 12-month health outcomes, we expect to be completed by the end of next year.”
The IDEAS team is also looking at a furthering the investigation with a study called, aptly, “NEW IDEAS.” That would reach out to recruit the minorities that were so underrepresented in the main study and include patients with early-onset MCI or dementia. Building up a library of DNA and blood plasma samples might also fit into the new project.
IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.
REPORTING FROM CTAD
Key clinical point: Amyloid PET imaging can refine equivocal dementia diagnoses.
Major finding:
Study details: The IDEAS study has thus far accrued data on 11,409 subjects.
Disclosures: IDEAS is a funding collaboration of the Centers for Medicare & Medicaid Services, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.