Intranasal Insulin for the Treatment of HAND

HIV-associated neurocognitive disorders (HAND) are characterized by disabling cognitive,
behavioral, and motor dysfunction and can occur in individuals with HIV even while taking
combination antiretroviral therapy (ART). The mechanisms for these residual impairments are
not fully understood, but appear to involve poor penetrance of ART drugs into the central
nervous system (CNS) and the resulting brain sanctuary for inadequately suppressed HIV
infection with associated sustained inflammation. Adjunctive therapies with targeted
neuroprotective agents are critically needed for the treatment of HAND. Insulin is involved
in multiple CNS functions including food intake, metabolism, learning, and memory. Insulin
has neuroprotective properties demonstrated in cell culture experiments and in vivo models,
which provide strong evidence for its use as a therapeutic agent to treat HAND.

Insulin modifying therapy (IMT) includes intranasal insulin administered by a novel nasal
drug delivery device. IMT may play important roles in neuronal plasticity and survival by
protecting hippocampal neurons against oxidative stress and apoptotic cell death induced by
glutamate neurotoxicity. Previous studies support the proposed early phase trial of IMT as a
novel therapeutic agent for HAND.

This double-blinded placebo-controlled clinical trial evaluates safety of intranasal insulin
at the daily dose of 40 IU and will provide initial data for assessing safety and efficacy.
The protocol measures safety by incidence and frequency of adverse events. Clinical effects
of IMT over the 24-week trial period are measured by change in neurocognitive and functional
testing results, as well as several novel radiological and cerebrospinal fluid (CSF)
surrogate markers. Outcomes from these studies could have important implications for the
design of future studies with IMT and other neuroprotective compounds for HAND.

Inclusion Criteria:

- Must have HIV,

- Capable of providing informed consent,

- Between the ages of 18-69 years,

- Evidence of problems with memory, speed, and brain function,

- Same HIV medications for at least 6 months (180 days) prior to study entry, with no
plans to change the medications over the study period,

- The following blood lab values within 2 weeks prior to study entry: hemoglobin > 8.9
g/dl, absolute neutrophil count > 500 cells/mm3, platelet count > 50,000 cells/mm3,
alanine aminotransferase (ALT) < 2.5 X upper limit of normal, alkaline phosphatase < 3
X upper limit of normal, serum creatinine ≤ 2 X upper limit of normal,

- Negative pregnancy test (for women who could become pregnant),

- Able and willing to use an intranasal device for taking the study drug without
complications (e.g., no history of traumatic obstruction to nasal passage, chronic
sinus infections, severe and symptomatic seasonal allergies, etc.),

- Currently suppressed blood HIV viral load (undetectable or <400 copies/mL).

Exclusion Criteria:

- Current or past opportunistic infection of the brain,

- History or current clinical evidence of schizophrenia,

- History of chronic neurological disorder, such as multiple sclerosis or uncontrolled
epilepsy,

- Active symptomatic AIDS defining opportunistic infection within 30 days prior to study
entry,

- History of an uncontrolled medical or psychiatric illness which in the opinion of the
investigators would constitute a safety risk for patients or interfere with the
ability of a participant to complete the study,

- History of diabetes or treatment with insulin or an oral hypoglycemic agent,

- Amylase/lipase elevation (≥ 2 X upper limit of normal) within 14 days prior to
starting study drug,

- Detectable plasma HIV RNA test ≥400 copies/mL within 6 months prior to
baseline/randomization,

- History of any endocrine related cancer, including any thyroid tumor,

- Current use of cocaine, heroin, or methamphetamine. Current use will be defined and
determined by any evidence of such use within the two years (730 days) prior to study
enrollment; evidence includes but is not limited to urine drug toxicology testing by
the study team at screening and pre-entry visits,

- Presence of other conditions that significantly affect and complicate performance on
neurocognitive tests (such as, learning disabilities, history of severe alcohol abuse,
head injury with trauma to the brain and loss of consciousness >30 minutes).