Intranasal Treatment of HIV-associated Neurocognitive Disorders

Study Overview
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Brief Summary
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This study aims to see whether intranasal insulin is an effective treatment for problems with memory, concentration, slowed thinking, or any other cognitive function in people living with HIV/AIDS. This group of signs and symptoms are called 'HIV-associated neurocognitive disorders' or HAND. HAND can affect people living with HIV/AIDS even when they receive potent anti-HIV treatments. Treatment of HAND by specific medication or other means is not yet available. Intranasal insulin treatment has virtually no side-effects, and has already been tested in people with Alzheimer's disease, where it showed beneficial effects on memory, mood and quality of life

Detailed Description
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This study is designed as a prospective, double-blinded pilot study of intranasal (IN) insulin versus placebo in people with HAND (n = 20) on stable ART medication. Participants will be randomly assigned to one of two groups: 40 IU IN insulin R twice daily, or matched-volume placebo, which will be administered twice daily, taken after breakfast and again after dinner using a nasal delivery device. Serum glucose will be tested for hypoglycemia one hour after the initial administration of IN insulin or placebo and after administration at Weeks 1, 2, and 3. If the dose is tolerated and no side effects are reported the participant will continue in the study. If the dose is not tolerated due to hypoglycemia then the participant will be withdrawn from the study. The objectives of this study are as follows: Primary: Determine if IN insulin treatment administered twice daily for 4 months reduces overall neurocognitive deficits (based on the global z-score in people with HAND). Secondary: Measure effects of IN insulin on individual neuropsychological domains (e.g., memory, processing speed, executive functions, motor functions) and on HAND disease progression; Define impacts of IN insulin on quality of life and mood in people with HAND; Investigate IN insulin's effects on HAND biomarker profiles in urine and blood.

Official Title
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HAND IN Insulin-001: Intranasal Treatment of HIV-associated Neurocognitive Disorders

Conditions
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HIV Associated Neurocognitive Disorder (HAND)

Intervention / Treatment
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* Biological: IN insulin
* Biological: Sterile Saline placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented HIV-1 infection Maintained on stable ART for ≥6 months (defined as undetectable viral load) HAND-MND or -ANI diagnosis with evidence of clinical onset or progression within the prior 2 years, based on established criteria Currently followed at the Southern Alberta Clinic (SAC; Calgary, AB, Canada) Exclusion Criteria: HAND with a) changed dose of any medication for HIV-1 infection with a corresponding increase in viral load (e.g., ART), or b) secondary therapies for HAND (e.g., memantine, amphetamines). Advanced liver, renal or lung disease, cancer or diabetes requiring insulin Secondary diagnosis of neurocognitive impairment or other major neuropsychiatric illness such as epilepsy, Alzheimer's or Parkinson's diseases, major depression (PHQ-9 score >10), or schizophrenia Central nervous system lesion (diagnosed by neuroimaging) that may impair cognition Previous allergic reaction to insulin or any of the carrier components. Education < 9 years or inability to read and write English fluently Uncontrolled HIV-1 or hepatitis C co-infection Inability to perform NP or questionnaire measures, functional illiteracy Past or current substance abuse that could interfere with the study assessments as determined by the PI Marijuana use on the day of NP testing Uncontrolled cardiovascular disease (hypertension, coronary or peripheral artery disease)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Arm 1: Drug: IN insulin Dose: Twice daily IN insulin R at 40 IU (n=10) twice daily using a nasal delivery device. IN insulin R will be administered twice daily. Arm 2: Drug: Sterile Saline placebo Dose: Placebo (Sterile Saline placebo, matched volume; (n=10) twice daily using nasal delivery device.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IN insulin 40 IU<br>Drug: IN insulin Dosage form: intranasal Dose: 40 IU Frequency: bid Duration: 16 weeks | Biological: IN insulin<br>* IN insulin twice daily taken after breakfast and again after dinner using the nasal delivery device.<br>* Other names: Intranasal Humulin R;|
| Placebo Comparator: IN Sterile Saline<br>Drug: Sterile Saline Dosage form: intranasal Frequency: bid Duration: 16 weeks | Biological: Sterile Saline placebo<br>* Sterile Saline placebo twice daily taken after breakfast and again after dinner using the nasal delivery device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Global Neurocognitive Performance from Baseline | Change in overall neurocognitive function as measured by the global z score. The global z score is one measurement calculated as the average of z scores from each domain tested. | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Neurocognitive Performance: Memory | Change from baseline in the overall z score for the memory domain, calculated as the average of z scores from: Hopkins Verbal Learning Test, Logical Memory Test, and Brief Visual Memory Test (immediate and delayed recall). | 18 weeks | 
| Change from Baseline in Neurocognitive Performance: Executive Function | Change from baseline in the overall z score for the executive function domain, calculated as the average of z scores from: D-KEFS Trail-making Task (Letter-Switching) and Color-Word Interference (Stroop). | 18 weeks | 
| Change from Baseline in Neurocognitive Performance: Attention | Change from baseline in the overall z score for the attention domain, calculated as the average of z scores from: Symbol Digit Modalities Test, D-KEFS Trail-making Test (Number), and Color-Word Interference (Color and Word Reading). | 18 weeks | 
| Change from Baseline in Neurocognitive Performance: Motor Function | Change from baseline in the overall z score for the motor function domain, calculated as the average of z scores from: grooved pegboard completion times for dominant and non-dominant hands. | 18 weeks | 
| Change from Baseline in Neurocognitive Performance: Language | Change from baseline in the overall z score for the language domain, calculated as the average of z scores from: D-KEFS Letter and Category Verbal Fluency Tasks | 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurocognitive impairment, Intranasal insulin, Neurocognitive Disorder, Cognition, Memory, HIV-1