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protocol being rewritten and submitted as new study
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Humulin® R U-100 | Experimental | Twenty randomly assigned participants with Alzheimer's disease or mild cognitive impairment will receive intranasal administrations of Humulin® R U-100 (40 IU) four times daily for 3 weeks. |
|
| Placebo | Placebo Comparator | Twenty randomly assigned participants with Alzheimer's disease or mild cognitive impairment will receive intranasal administrations of placebo (insulin diluent) four times daily for 3 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Insulin (Humulin® R U-100) | Drug | Participants will administer 40 IU of Humulin® U-100 insulin four times per day with an intranasal delivery device. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Prescribed Dose Taken | 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. | Week 4 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the Preclinical Alzheimer Cognitive Composite 5 (PACC5) Z-Score | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Quick Dementia Rating Scale (QDRS) Score | 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Suzanne Craft, PhD | Wake Forest University Health Sciences | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21514249 | Background | Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):270-9. doi: 10.1016/j.jalz.2011.03.008. Epub 2011 Apr 21. | |
| 3758265 |
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| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D003704 | Dementia |
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| ID | Term |
|---|---|
| D007328 | Insulin |
| ID | Term |
|---|---|
| D011384 | Proinsulin |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
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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.
| Placebo | Drug | Participants will administer placebo (insulin diluent) four times per day with an intranasal delivery device. |
|
|
| Aptar Pharma CPS Intranasal Delivery Device | Device | Participants will be assigned to receive Humulin® insulin or placebo administered through the Aptar Pharma CPS intranasal delivery device. |
|
| Baseline to Week 8 |
| Change in the 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog 14) Score | 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. | Baseline to Week 8 |
| Change in Cerebrospinal Fluid (CSF) Insulin Levels | 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. | Baseline to Week 8 |
| Change in amyloid β-peptide (Aβ) 40 (Aβ40) in Cerebrospinal Fluid (CSF) | 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. | Baseline to Week 8 |
| Change in amyloid β-peptide (Aβ) 42 (Aβ42) in Cerebrospinal Fluid (CSF) | 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. | Baseline to Week 8 |
| Change in Cerebrospinal Fluid (CSF) Levels of Total Tau | 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. | Baseline to Week 8 |
| Change in Cerebrospinal Fluid (CSF) Levels of Phospho-Tau 181 | 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. | Baseline to Week 8 |
| Change in Cerebrospinal Fluid (CSF) Levels of Phospho-Tau 217 | 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. | Baseline to Week 8 |
| Baseline to Week 8 |
| Change in Patient Health Questionnaire (PHQ-9) Score | 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. | Baseline to Week 8 |
| Change in Generalized Anxiety Disorder scale-7 (GAD-7) Score | 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. | Baseline to Week 8 |
| Change in PROMIS Sleep Disturbance Questionnaire Score | 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. | Baseline to Week 8 |
| Change in the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-ADL-MCI) | 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. | Baseline to Week 8 |
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| D001927 |
| Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D006728 |
| Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |