Intranasal Insulin for Improving Cognitive Function in Multiple Sclerosis

Cognitive impairment is common in and devastating to people with MS. MS is a common, chronic,
central nervous system (CNS) disease characterized by inflammation, demyelination, and
neurodegeneration. One of the most devastating symptoms of this disease is impaired cognitive
function, which is common and present in over 60% of individuals with MS. MS-related
cognitive impairment is associated with lowered quality of life and reduced functional
capacity, including loss of employment, impaired social relationships, compromised driving
safety, and poor adherence to treatment. Impaired cognitive functioning has been observed
early in the disease, sometimes even before diagnosis, and cognitive function has been shown
to decline longitudinally, both over the short- and long-term. Several cognitive domains are
impacted in people with MS, including attention, memory, executive functioning, and
especially processing speed.

To date, multiple pharmacologic interventions have been assessed with disappointing results.
There was no significant difference between treatment and placebo for cognition in randomized
control trials of donepezil, aminopyridines, gingko biloba, and memantine. Psychostimulants
demonstrated some efficacy, but only in secondary outcome measures. Behavioral interventions
show promise but are understudied. Furthermore, cognitive rehabilitation is often time
consuming, costly, and not universally available. Hence, there is an urgent need to identify
or develop novel therapies that can help improve cognitive function in MS.

Intranasal insulin is extremely safe and tolerable in other populations, allowing for
concentrated delivery to the nervous system. An intranasal delivery system provides a
non-invasive way to bypass the blood-brain barrier and allow rapid delivery of a medication
to the CNS via the olfactory and trigeminal perivascular channels.The main advantage of the
delivery system is reducing systemic side effects via limiting a medication's exposure to
peripheral organs and tissues.

Insulin administration has been shown to improve memory and learning in healthy people and in
those with neurodegenerative diseases. Intranasal insulin has been shown to have
neuroprotective and restorative effects in several human clinical trials. Overall, findings
suggest that intranasal insulin not only affects cognitive function acutely, but that over
time, there may be associated structural changes that lead to a more permanent treatment
benefit. Cognitive dysfunction is very common in MS and can be devastating, therefore a
treatment intervention (i.e., intranasal insulin) can help both acutely and longitudinally.

The primary aim of this study is to assess the safety and tolerability of intranasal insulin
in people with MS. The secondary aim is to evaluate if intranasal insulin improves learning
and memory in people with MS. The third aim is to evaluate the impact of intranasal insulin
on measures of oxidative stress, axonal injury, cellular stress, and energy metabolism in MS.

Inclusion Criteria:

- Meets 2010 criteria for MS

- No relapse in past 3 months

- At least mild cognitive impairment (based off of SDMT/PST score)

- Capacity to learn and self-administer intranasal insulin/placebo, or presence of a
caregiver with such capacity who is willing to do it for the duration of the trial

- Untreated/on the same MS therapy for at least 6 months, with no anticipated change in
the next year

- Willing to prevent pregnancy during study if female of childbearing potential

Exclusion Criteria:

- Current, active major depression

- No tricyclic antidepressant or anticonvulsant (except carbamazepine, pregabalin or
gabapentin) use within 6 weeks of screening; if on oxybutynin or tolterodine, on
stable dose for > 6 months without plans for changing dose in next year

- If taking selective serotonin (± norepinephrine) reuptake inhibitors, pregabalin,
gabapentin, sympathomimetic, monoamine oxidase inhibitor, antipsychotic, amantadine,
cholinesterase inhibitor, memantine, modafanil, armodafinil, or evening short-acting
benzodiazepines, on stable dose for 6 weeks or greater

- Pregnant or nursing

- THC; illicit drug or alcohol abuse in past 3 months

- History of diabetes mellitus or insulin resistance

- Active liver disease, stage IV/V kidney disease or severe metabolic derangements

- CNS disorder other than MS or headache