Alzheimer Disease, Early Onset, Cognitive Impairment, Mild Cognitive Impairment
Conditions
Keywords
Intranasal Delivery of Insulin, Cognitive Testing, Nasal Insulin
Brief summary
The SNIFF 3-Week Aptar Device study will involve using a device to administer insulin or placebo through each participant's nose or intra-nasally. Insulin is a hormone that is produced in the body. It works by lowering levels of glucose (sugar) in the blood. This study is measuring how much insulin the device delivers. In addition, this study will look at the effects of insulin or placebo administered intra-nasally using an intranasal delivery device on memory, blood, and cerebrospinal fluid (CSF).
Detailed description
The proposed study will examine whether an intranasal delivery device can be used by adults with preclinical Alzheimer's disease (cognitively normal but with abnormal brain levels of the hallmark peptide Aβ) to reliably deliver insulin or placebo four times daily over a 4 week period. We will also examine effects of treatment on cognition, CSF biomarkers, and cerebral perfusion. If successful, information gained from the study will inform the design of future Phase III trials of intranasal insulin.
Interventions
Participants will administer 40 IU of Humulin® U-100 insulin four times per day with an intranasal delivery device.
DRUGPlacebo
Participants will administer placebo (insulin diluent) four times per day with an intranasal delivery device.
Participants will be assigned to receive Humulin® insulin or placebo administered through the Aptar Pharma CPS intranasal delivery device.
Sponsors
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Neither participants or site personnel will know which drug intervention (insulin or placebo) is being administered. Exceptions will be the Study Nurse who is directly involved in preparing the insulin or placebo.
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 55 to 85 (inclusive) 2. Fluent in English 3. Cognitively normal or diagnosis of amnestic mild cognitive impairment (aMCI) or mild Alzheimer's disease (AD) 4. Amyloid positive by positron emission tomography (PET) or cerebrospinal fluid (CSF) criteria 5. Stable medical condition for 3 months prior to screening visit 6. Stable medications for 4 weeks prior to the screening and study visits (exceptions may be made on a case by case basis by the study physician) 7. Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the study physician
Exclusion criteria
1. A diagnosis of dementia other than Alzheimer's disease (AD) 2. History of a clinically significant stroke 3. Current evidence or history in past two years of epilepsy, head injury with loss of consciousness, any major psychiatric disorder including psychosis, major depression, bipolar disorder 4. Diabetes (type I or type II) insulin-dependent and non-insulin-dependent diabetes mellitus 5. Current or past regular use of insulin or any other anti-diabetic medication within 2 months of screening visit 6. History of seizure within past five years 7. Pregnancy or possible pregnancy 8. Use of anticoagulants 9. Residence in a skilled nursing facility at screening 10. Use of an investigational agent within two months of screening visit 11. Regular use of alcohol, narcotics, anticonvulsants, anti-parkinsonian medications, or any other exclusionary medications (exceptions may be made on a case by case basis by the study physician)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Prescribed Dose Taken | Week 4 | Participant self-reported medication adherence information will be calculated by study staff on a 0%-100% scale. A score below 80% indicates low medication adherence and a score of 80% or higher indicates high medication adherence. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cerebrospinal Fluid (CSF) Insulin Levels | Baseline to Week 8 | Measurement of the levels of insulin in cerebrospinal fluid (CSF) after being delivered with the intranasal delivery device. This will help to determine the ability of the intranasal delivery device to increase levels of insulin in CSF. |
| Change in amyloid β-peptide (Aβ) 40 (Aβ40) in Cerebrospinal Fluid (CSF) | Baseline to Week 8 | Cerebrospinal fluid (CSF) samples will be used to measure the levels of amyloid β-peptide (Aβ) 40. CSF Aβ40 is a key Alzheimer's disease (AD) biomarker that reflects pathological aggregation of amyloid in the brain. |
| Change in amyloid β-peptide (Aβ) 42 (Aβ42) in Cerebrospinal Fluid (CSF) | Baseline to Week 8 | Cerebrospinal fluid (CSF) samples will be used to measure the levels of amyloid β-peptide (Aβ) 42. CSF Aβ42 is a key Alzheimer's disease (AD) biomarker that reflects pathological aggregation of amyloid in the brain. |
| Change in Cerebrospinal Fluid (CSF) Levels of Total Tau | Baseline to Week 8 | Cerebrospinal fluid (CSF) samples will be used to measure the levels of total tau protein in the brain to assess impact on brain tau as a relevant Alzheimer's Disease (AD) biomarker. |
| Change in Cerebrospinal Fluid (CSF) Levels of Phospho-Tau 181 | Baseline to Week 8 | Cerebrospinal fluid (CSF) samples will be used to measure the levels of phospho-tau 181 protein in the brain to assess impact on brain tau as a relevant Alzheimer's Disease (AD) biomarker. |
| Change in Cerebrospinal Fluid (CSF) Levels of Phospho-Tau 217 | Baseline to Week 8 | Cerebrospinal fluid (CSF) samples will be used to measure the levels of phospho-tau 217 protein in the brain to assess impact on brain tau as a relevant Alzheimer's Disease (AD) biomarker. |
| Change in the Preclinical Alzheimer Cognitive Composite 5 (PACC5) Z-Score | Baseline to Week 8 | Cognition will be measured using the PACC5 scale, which includes the free/cued selective reminding test, delayed paragraph recall, digit-symbol substitution, mini mental state score, and the category fluency task. The PACC5 is a composite score comprised of measures of global cognition, memory, and executive function. The score reflects an averaged z-score, with higher scores indicating better cognitive performance. |
| Change in the 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog 14) Score | Baseline to Week 8 | A psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment. Scores from the original portion of the test range from 0 (best) to 65 (worse), and are added to the mean of the words not immediately recalled (max of 10) and the number of items not recalled after a delay (ranging from 0-10) all total the maximum score of 85. A positive change indicates cognitive worsening. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Generalized Anxiety Disorder scale-7 (GAD-7) Score | Baseline to Week 8 | Changes in anxiety will be measured using the Generalized Anxiety Disorder Scale (GAD-7), which contains 7 items with total scores ranging from 0 to 21. Scores of 5, 10, and 15 are cut-offs for mild, moderate, and severe anxiety, respectively. |
| Change in PROMIS Sleep Disturbance Questionnaire Score | Baseline to Week 8 | A questionnaire to assess self-reported quality of general sleep and sleep disturbance. Each item on the form is rated on a 5-point scale (1=never; 2=rarely; 3=sometimes; 4=often; and 5=always) with a range in score from 8 to 40 with higher scores indicating greater severity of sleep disturbance. |
| Change in the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-ADL-MCI) | Baseline to Week 8 | An interview-based assessment of information provided by the study partner (informant). The total scores based on 18 items on the scale range from 0 to 53 with lower scores representing greater impairment. |
| Change in Quick Dementia Rating Scale (QDRS) Score | Baseline to Week 8 | The QDRS (Galvin, 2015) is a clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe (Clinical Dementia Rating score of 0, 0.5, 1, 2, or 3, respectively). The score assesses six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. At Screening the QDRS global score will be used for eligibility purposes. For all other administrations, the 6 domain scores will be summed to get the QDRS Sum of Boxes (SB) score. Sum of boxes score ranges from 0-100 with a high score meaning more severe dementia. |
| Change in Patient Health Questionnaire (PHQ-9) Score | Baseline to Week 8 | The Patient Health Questionnaire (PHQ-9) is a 9-item, validated measure of depression severity. Respondents indicate how bothered by problems they are on a scale from 0 (not at all) to 3 (nearly every day). Total scores range from 0 to 27, where higher scores indicate more severe depression. |
Outcome results
None listed