Intranasal Insulin and Post-stroke Cognition: A Pilot Study

Hypothesis: Intranasal insulin will improve post-stroke cognitive impairment if administered
in the early post-acute stroke phase compared with placebo.

Design: Block randomized, double-blind placebo-controlled trial of 40 patients, 20 per group.

Study population: Ischemic stroke patients presenting within 48 hours of symptom onset and
without moderate to severe aphasia or homonymous hemianopia who have evidence of cognitive
impairment on the Montreal Cognitive Assessment (MoCA).

Recruitment: Patients identified during the acute hospitalization for ischemic stroke,
inpatient rehabilitation, or in the post-stroke follow-up clinic. Patients from other
hospitals and clinics are also eligible. Eligibility will be assessed through screening MoCA
and if in the target range, will be invited to participate in the study.

Consent: Patients will sign informed consent if eligible.

Randomization and Blinding: The participant will be randomized and undergo the full baseline
cognitive battery. Caregivers will also sign a separate consent to complete the Caregiver
Strain Index. Subjects will be randomized to intranasal insulin (20 IU BID) vs saline BID
according to a stratified permuted block randomization of 4 as per our statistician,
stratified by age 40 to 69 years vs > 70 years) and presence of language deficit (based on
NIHSS) at the time of randomization. Insulin and saline will be packaged in identical
single-dose ampules that will be opened and inserted into the chamber of the VianaseTM
device. Ampoules will be dispensed in 3 week supplies at each study visit. Package labels
will instruct participants to administer each dose 30-60 minutes after breakfast and dinner.
If a dose is missed, it will not be replaced. The insulin and saline will be identical in
packaging except for randomization code. Patients/caregivers, investigators, and outcome
assessors will be masked to the group assignment. All subjects will receive their first dose
in the clinic and wait for 2 hours to determine any adverse effects of the inhaled dose,
while remaining blinded to the treatment. The glucose level will be measured with the
glucometer to monitor for hypoglycemia and documented. All subjects will additionally check
peak dose blood sugar levels with a glucometer, 3 times per week during insulin or saline
treatment. The patients and caregivers will receive a handbook which describes the method for
loading the device, inhalation, methods for fingersticks, use of the glucometer and test
strips, a blood sugar log, and the signs and symptoms of hypoglycemia. They will also
document any other adverse effects on the weekly log.

Procedures: Cognitive impairment measured early after stroke predicts functional outcomes in
stroke patients at 13 months. Furthermore, waiting until 6 weeks after the stroke to conduct
baseline cognitive testing and treatment allows enough recovery and completion of intensive
rehabilitation for those patients who may not be able to complete cognitive testing
immediately after stroke, but takes advantage of the potential benefits of insulin in the
early phase, shown in animal studies. In addition, we potentially reduce the variability of
the biomarkers by avoiding the acute phase of stroke. The frequency of cognitive testing is
based on trials of intranasal insulin for MCI and AD.

Patients with a history of psychiatric medication use for the management of mental and
emotional disorders prior to their stroke will not be excluded from the study. However, as
these medications may have an effect on cognitive testing, initiation of psychiatric
medications should be avoided from the time of study enrollment through the post wash out
period (9 weeks total) unless it is clearly indicated to be in the patient's best interest.
Patients will be informed of the prohibited medications during consent and will be asked to
immediately inform the study team of any new medications or changes in existing medications.

Baseline Data collection. We will collect the baseline data described below as in the VCI
Harmonization standards:

Demographics: Birth date, sex, race/ethnicity, years in current country of residence, number
of years of education, occupation, literacy, living situation and level of independence, type
of residence, marital status, and name and contact information for a family member or
caregiver will be collected.

Proxy/informant information collected: Birth date, sex, race/ethnicity, relationship and
length of time of relationship with the patient, education, and living status with respect to
the subject.

Family history information collected: First-degree relatives with stroke, myocardial
infarction, and dementia, approximate age at onset, and age at death.

Stroke hospital data collected: Severity (NIHSS) at onset, location of stroke, vascular
territory, modified Rankin score at discharge, short physical performance battery score,
length of stay, stroke complications, stroke prevention medications at discharge, stroke risk
factors (diabetes, hypertension, hyperlipidemia, smoking, alcohol/substance abuse, atrial
fibrillation, carotid stenosis, hypercoagulable state), and stroke subtype (NINDS
classification).

Intranasal insulin administration: We will use an innovative investigational device developed
by Kurve Technology (Fig 5A). Typical spray bottle administration results in large droplets
that penetrate only within the first 20% of the lower nasal cavity, and due to gravity and
insufficient airflow, ~90% of the droplets wind up in the stomach (Fig.5B). The ViaNaseTM
device delivers a substance throughout the nasal cavity, to the olfactory region and
paranasal sinuses, thereby maximizing access to nose-to-brain channels (Fig.5C). This
distribution occurs because droplet size is adjusted according to the weight of the
substance, through an individually optimized droplet generator resulting in maximal vortical
distribution (Fig.5D). We have used the ViaNaseTM device with excellent results in two pilot
trials (described above).12,13 A total volume of 2 mL of insulin or placebo (saline) will be
administered each time. Caregivers will supervise participants in administering intranasal
treatment 2 times per day, after breakfast and dinner. Participants and caregivers will be
trained in use of the delivery device. In previous studies, participants with aMCI/AD have
found the device to be easy and pleasant to use, with compliance rates of 95 to 97%.

Cognitive Outcome Analysis: The analysis will be based on intention to treat. The primary
outcomes are analyzed via composite z scores at 3 weeks of treatment in both groups.

The summary scores of the SIS, IADL scale and SIS-16 will be compared from baseline to 3
weeks post treatment in both groups.

Functional covariates: Disability and physical function measures will be collected to
understand the trajectory of motor recovery and will be mapped to the cognitive trajectory
from baseline (2 weeks to 20 weeks post-stroke). Exploratory analyses will be performed to
determine whether INI leads to an improvement in IADLs, SIS-16, and mRS.

Statistical Analysis: The 3 week intervention effect of INI on the cognitive outcomes will be
assessed using analysis of covariance (ANCOVA) adjusting for age, language deficit, and
baseline cognitive score. We will assume a Type I error rate alpha = 0.05 for all analyses.
Adjusting for baseline characteristics will help attenuate the potential effect of
differential dropout, but we will conduct a sensitivity analysis using multiple imputation to
ensure dropout does not unduly affect our results. The observed estimates, standard
deviations, and dropout rates will be used for the design of future studies of INI treatment
for stroke patients.

Exploratory analyses will examine response by subgroup for evidence of an enhanced treatment
effect, including subgroups defined by participant age (<70 vs. >70 years), baseline
cognitive impairment and the presence or absence of any degree of language deficit (aphasia).
Covariates will be utilized so that they do not overlap with clinical subgroups. Because of
the relatively small sample size, if the prespecified subgroups based on continuous
characteristics are not sufficiently large, new clinically meaningful subgroups may be formed
for exploratory analyses.

Power Analysis: The primary purpose of the pilot study is to demonstrate feasibility and
safety. The proposed study will collect data to estimate power in future trials, identify
instruments most sensitive to the proposed cognitive effects, and anticipate recruitment and
retention rates in the target population. However, the proposed study will have 83% power to
detect a 1 standard deviation difference in cognitive scores between groups at 3 weeks (i.e.
effect size = 1.0), assuming normally distributed outcomes, alpha = 0.05, and a 10% dropout
rate.

Inclusion Criteria:

- 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.

Exclusion Criteria:

- 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