Intranasal Insulin and Post-stroke Cognition: A Pilot Study

NCT02810392 | Completed Phase 2 Results FDA Drug

• 1 other identifier: IRB00029022
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Almost two-thirds of survivors have cognitive impairment (CI), manifested as memory, language, and judgement problems. Post-stroke CI at 2 weeks is a significant predictor of long-term functional outcome, and more generally, cognitive impairments have a major impact on functional outcome and ability to participate in rehabilitation. CI is associated with increased systemic inflammation. Intranasally-administered insulin is a promising new therapy for enhancing memory in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), shown in multiple randomized controlled studies. Likely mechanisms of benefit are intranasal insulin's ability to restore normal cerebral insulin signaling. Based on the overlap in cerebral insulin resistance that occurs in both AD and post-stroke CI, we have designed an innovative proof-of-concept, feasibility trial designed to provide pilot data as to whether post-stroke survivor CI and caregiver burden is improved with intranasal insulin early after stroke. We will explore the impact of intranasal insulin on inflammatory biomarkers, since inflammation is a major underlying cause of CI, as shown by others and in our preliminary studies of VCAM-1. Specific Aims are: 1. Determine if patients with ischemic stroke randomized to intranasal insulin 20 IU BID for 3 weeks have improved cognition, compared to patients who receive intranasal saline. Primary outcome is a composite of (a) memory and executive function z scores. 2. To assess the impact of intranasal insulin vs saline on change in inflammatory biomarker levels (VCAM-1, TNF-alpha, TNFR-I and II) before and after the treatment period. 3. To measure differences in burden among caregivers of participants in the intranasal insulin vs intranasal saline groups. We will prospectively randomize 40 subjects to intranasal insulin (40 IU) vs saline treatment. Following baseline cognitive testing 2 weeks post stroke, subjects will receive the assigned treatment for 3 weeks, followed by a 3-week washout period, with cognitive testing performed after the treatment and washout periods and again at 20 weeks. The proposed study will provide data on a promising method for treating cognitive function in stroke patients. If effective, our pilot data will set the stage for larger phase III clinical trials.

Conditions

Stroke

Outcome Measures

Primary Outcomes (9)

• Composite of Memory t Scores

  Hopkins Verbal Learning Test-Revised (HVLT-R) verbal learning and memory and available to facilitate repeat administration in future testing (10 minutes with delay and recognition). The delayed recall is used as the outcome in this study. Brief Visual Memory Test-Revised (BVMT-R) is a measure of nonverbal learning and memory captured with immediate and delayed free recall trials, and a recognition memory task (10 minutes with delay and recognition). The retained score normalized by age, is used as the outcome for this study. The t scores for both HVLT-R delayed recall and BVMT-R retained are normalized from the raw scores based on age. The t score ranges from 0-100 with 0 denoting a worse outcome. The Composite is the average of the mean t scores for each component.

  baseline

• Composite of Memory t Scores

  Hopkins Verbal Learning Test-Revised (HVLT-R) verbal learning and memory and available to facilitate repeat administration in future testing (10 minutes with delay and recognition). The delayed recall is used as the outcome in this study. Brief Visual Memory Test-Revised (BVMT-R) is a measure of nonverbal learning and memory captured with immediate and delayed free recall trials, and a recognition memory task (10 minutes with delay and recognition). The retained score is used as the outcome for this study. The t scores for both HVLT-R delayed recall and BVMT-R retained are normalized from the raw scores based on age. The t score ranges from 0-100 with 0 denoting a worse outcome. The Composite is the average of the mean t scores for each component.

  week 3

• Composite of Memory t Scores

  Hopkins Verbal Learning Test-Revised (HVLT-R) verbal learning and memory and available to facilitate repeat administration in future testing (10 minutes with delay and recognition). The delayed recall is used as the outcome in this study. Brief Visual Memory Test-Revised (BVMT-R) is a measure of nonverbal learning and memory captured with immediate and delayed free recall trials, and a recognition memory task (10 minutes with delay and recognition). The retained score is used as the outcome for this study. The t scores for both HVLT-R delayed recall and BVMT-R retained are normalized from the raw scores based on age. The t score ranges from 0-100 with 0 denoting a worse outcome. The Composite is the average of the mean t scores for each component.

  week 6

• Composite of Executive Function t Scores

  The Trail Making test-B is a test of sequencing between numbers and letters, and the score is the amount of time needed to complete the test. The t score is the raw score for time to completion and errors, normalized by age and education, and ranges from 0 (poor performance) to 100 (good performance). WAIS Digit Span subtest Reverse is a measure of working memory, and requires repetition of increasingly longer strings of digits in the reverse order. The t scores are raw scores normalized by age and range from 0 to 100. WAIS-III Digit-Symbol Coding is a measure of visuomotor processing speed, and requires involves rapidly coding geometric symbols given a number, by using a legend of number-symbol pairs at the top of the page. T scores are raw scores normalized by age, and range from 0 to 100. The composite outcome included average of the mean t scores for Trailmaking B, Digit span reverse, and digit-symbol coding.

  baseline

• Composite of Executive Function z Scores

  The Trail Making test-B is a test of sequencing between numbers and letters, and the score is the amount of time needed to complete the test. The t score is the raw score for time to completion and errors, normalized by age and education, and ranges from 0 (poor performance) to 100 (good performance). WAIS Digit Span subtest Reverse is a measure of working memory, and requires repetition of increasingly longer strings of digits in the reverse order. The t scores are raw scores normalized by age and range from 0 to 100. WAIS-III Digit-Symbol Coding is a measure of visuomotor processing speed, and requires involves rapidly coding geometric symbols given a number, by using a legend of number-symbol pairs at the top of the page. T scores are raw scores normalized by age, and range from 0 to 100. The composite outcome included average of the mean t scores for Trailmaking B, Digit span reverse, and digit-symbol coding.

  week 3

• Composite of Executive Function z Scores

  The Trail Making test-B is a test of sequencing between numbers and letters, and the score is the amount of time needed to complete the test. The t score is the raw score for time to completion and errors, normalized by age and education, and ranges from 0 (poor performance) to 100 (good performance). WAIS Digit Span subtest Reverse is a measure of working memory, and requires repetition of increasingly longer strings of digits in the reverse order. The t scores are raw scores normalized by age and range from 0 to 100. WAIS-III Digit-Symbol Coding is a measure of visuomotor processing speed, and requires involves rapidly coding geometric symbols given a number, by using a legend of number-symbol pairs at the top of the page. T scores are raw scores normalized by age, and range from 0 to 100. The composite outcome included average of the mean t scores for Trailmaking B, Digit span reverse, and digit-symbol coding.

  week 6

• Verbal Fluency

  These tasks of verbal fluency provide the subject one minute to say as many words as possible. For Animal Naming, any living creature is counted. For FAS, words beginning with a given letter (F, A, and then S) are counted excluding proper nouns, numbers, and variations of the same word. Raw scores are converted to t scores, normalized by age, and range from 0 (worse) to 100 (better) outcome.

  baseline

• Verbal Fluency

  These tasks of verbal fluency provide the subject one minute to say as many words as possible. For Animal Naming, any living creature is counted. For FAS, words beginning with a given letter (F, A, and then S) are counted excluding proper nouns, numbers, and variations of the same word. Raw scores are converted to t scores, normalized by age, and range from 0 (worse) to 100 (better) outcome.

  week 3

• Verbal Fluency

  These tasks of verbal fluency provide the subject one minute to say as many words as possible. For Animal Naming, any living creature is counted. For FAS, words beginning with a given letter (F, A, and then S) are counted excluding proper nouns, numbers, and variations of the same word. Raw scores are converted to t scores, normalized by age, and range from 0 (worse) to 100 (better) outcome.

  week 6

Secondary Outcomes (3)

• Montreal Cognitive Assessment (MoCA)

  Baseline, week 3, week 6

• Patient Health Questionnaire-9 Question (PHQ-9)

  Baseline, week 3, week 6

• Story Memory Recall

  baseline, week 3, week 6

Other Outcomes (3)

• Instrumental Activities of Daily Living Scale:

  baseline, week 3, week 6

• Modified Caregiver Strain Index

  baseline, week 3, week 6

• Modified Rankin Score (MRS)

  Baseline, week 3, week 6

Study Arms (2)

Intranasal Insulin

ACTIVE COMPARATOR

Intranasal Insulin (20 IU BID): Humulin insulin packaged is in single-dose ampules and inserted into the VianaseTM chamber. Ampoules are dispensed in 3 week supplies per study visit. Patients/caregivers, investigators, and outcome assessors are masked to group assignment. Subjects will receive their first dose in clinic, and wait 2 hrs to determine any adverse effects of inhaled dose. Glucose levels will be measured to monitor for hypoglycemia and documented. All subjects will check peak dose blood sugar levels with glucometer, 3 times per week during insulin treatment.

Drug: Intranasal Insulin

Intranasal Saline

PLACEBO COMPARATOR

Intranasal saline: Saline is packaged in single-dose ampules and inserted into the VianaseTM chamber. Ampoules are dispensed in 3 week supplies per study visit. Patients/caregivers, investigators, and outcome assessors are masked to group assignment. Subjects will receive their first dose in clinic, and wait 2 hrs to determine any adverse effects of inhaled dose. Glucose levels will be measured to monitor for hypoglycemia and documented. All subjects will check peak dose blood sugar levels with glucometer, 3 times per week during insulin treatment.

Drug: Intranasal saline

Interventions

Intranasal Insulin DRUG

Delivery is with the Vianase device, 20 IU twice daily for 3 weeks.

Also known as: Humulin insulin

Intranasal Insulin

Intranasal saline DRUG

Delivery is with the Vianase device, 0.5 cc of normal saline

Also known as: normal saline

Intranasal Saline

Eligibility Criteria

• Age: 40 Years - 89 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ischemic stroke and measurable deficit on the initial NIHSS (\> 1)
• Cognitive impairment within the 5th and 50th percentiles for age, race, and education based on Montreal Cognitive Assessment (MoCA) or 2 out of 5 delayed recall or less on the MoCA.
• Able to sign informed consent, have a caregiver, and live within a reasonable driving distance from Wake Forest Baptist Medical Center.

You may not qualify if:

• Patients under age 40 or 90 years or older
• Living in skilled nursing facility
• Severe stroke deficits at 4 weeks that prohibit participation in cognitive testing (global or receptive aphasia, or severe expressive aphasia)
• Diabetes requiring insulin
• Psychiatric disorders
• Severe head trauma
• Alcoholism
• Neurologic disorders other than stroke
• Renal disease
• hepatic disease
• chronic obstructive pulmonary disease
• unstable cardiac disease
• those with prior deficits in ADLs and IADLs

Sponsors & Collaborators

• Wake Forest University Health Sciences: lead

Study Sites (1)

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157-1043, United States

Location

MeSH Terms

Conditions

Stroke

Interventions

Insulin; Saline Solution

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Cheryl Bushnell, MD
• Organization: Wake Forest School of Medicine

cbushnel@wakehealth.edu

336-713-2983

Study Officials

• Cheryl Bushnell, MD

  Wake Forest University Health Sciences

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2016
• First Posted: June 23, 2016
• Study Start: April 1, 2016
• Primary Completion: March 4, 2020
• Study Completion: March 4, 2020
• Last Updated: May 13, 2021
• Results First Posted: May 13, 2021

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)