Intranasal Insulin and Post-stroke Cognition: A Pilot Study
Condition: Stroke
MeSH terms: Stroke
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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.
    

Intervention name(s): Intranasal Insulin; Intranasal saline
Intervention type(s): Drug; Drug
Intervention description(s): Delivery is with the Vianase device, 20 IU twice daily for 3 weeks.; Delivery is with the Vianase device, 0.5 cc of normal saline
Other intervention name(s): Humulin insulin; normal saline
Intervention MeSH terms: Insulin; Insulin, Globin Zinc
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment