Intranasal Insulin for the Treatment of HAND

Study Overview
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Brief Summary
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Infection with HIV (the virus that causes AIDS) can lead to problems with brain function, such as memory, concentration, judgment, and the speed or control of hands and legs. Neurologists have called this condition HIV-associated neurocognitive disorder (HAND). This research is being done to see if insulin taken through the nose as a spray (intranasal insulin) can help people with HIV who are having problems with memory and brain function, or HAND. Participants will be given either insulin or placebo. A placebo is an inactive substance that looks like the study drug, but does not contain study drug. For this research study, the placebo will be a clear, saline-based liquid spray that looks like the insulin spray but has no insulin. Participants will not be told whether they receive insulin or placebo during the study. All participants will take the intranasal spray twice a day, about 30 minutes after a meal. Participants will use a specialized intranasal drug administration device. The total daily dose of insulin is 40 IU split between 20 IU in the morning and 20 IU in the evening. Participants will take the intranasal spray for 24 weeks. The researchers will record symptoms and side effects during the study. Procedures include neurocognitive testing of memory and brain function, two optional lumbar punctures (spinal taps), two MRI brain scans, monthly blood draws, and clinical assessments.

Detailed Description
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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.

Official Title
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Clinical Trial of Intranasal Insulin for the Treatment of HIV-associated Neurocognitive Disorder (HAND)

Conditions
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HIV Dementia, HIV-Associated Cognitive Motor Complex

Intervention / Treatment
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* Drug: Insulin, intranasal
* Drug: Placebo, intranasal


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 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: Randomized double-blind placebo-controlled clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin, intranasal<br>Regular insulin, 20 IU intranasal twice a day for 24 weeks; 0.2 mL per dose | Drug: Insulin, intranasal<br>* Regular insulin administered by specialized, non-commercial intranasal drug delivery device<br>* Other names: Novolin R;|
| Placebo Comparator: Placebo, intranasal<br>Saline solution (placebo), intranasal twice a day for 24 weeks; 0.2 mL per dose | Drug: Placebo, intranasal<br>* Saline solution administered by specialized, non-commercial intranasal drug delivery device<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious Adverse Event Frequency | Number of documented serious adverse events per participant, mean | Total during 24-week trial | 
| Serious Adverse Event Frequency, Participant Count | Number participants with at least one documented serious adverse event, count | Total during 24-week trial | 
| Neurocognitive Performance: Global Deficit Score (GDS), Week 24 Visit Score Minus Baseline Score | Change in GDS, measured at two time points, baseline and Week 24 visits. GDS is a composite score based on neurocognitive test performance. The 14 data points that comprise the GDS include Hopkins Verbal Learning Test (trials 1-3 total score and delayed recall), Rey Complex Figure Test (copy and delayed recall), WAIS symbol-digit test, grooved pegboard (dominant and non-dominant), CalCAP (Choice reaction time and Sequential reaction time), Trail-making Test (Parts A and B), Stroop Color Interference Test (trial 3), timed gait (3 trials average), and verbal fluency (FAS). Raw scores were transformed to t-scores using age/education stratified normative data, then assigned a discrete value from 0 to 5 using the following t-score categorization: > or = 40 is '0', 35.00 to 39.99 is '1', 30.00 to 34.99 is '2', 25.00 to 29.99 is '3', 20.00 to 24.99 is '4', and <20 is '5'. The 14 individual scores were then averaged. A higher GDS is a worse outcome (0 = no deficits and 5 = maximum deficits). | Difference between baseline and week 24 visits | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurocognitive Performance: NPZ-8 Score, Week 24 Visit Score Minus Baseline Score | NPZ-8 score at 24 weeks minus baseline NPZ-8 score: The NPZ-8 is an average of 8 individual Z-scores, where higher values indicate greater neurocognitive performance (better outcome). The NPZ-8 represents the number of standard deviations an individual's performance is away from the mean (Z-score = 0) of age and education matched reference populations where performance worse than the mean had negative Z-scores (i.e. Z-scores were inverted for tests scored on speed). The NPZ-8 average is comprised of 8 data points from 6 tests: timed gait, WAIS symbol-digit, grooved pegboard dominant & non-dominant, CalCAP Choice & Sequential reaction times, and the Trail-making Test parts A & B. Raw scores were transformed to Z-scores for each test and then averaged to calculate the NPZ-8 score at each visit (Z-scores +/-3.5 standard deviations from mean limited to +/-3.5). Positive change in NPZ-8 from baseline to Week 24 indicated improved performance and negative change indicated worse performance. | Difference between baseline and week 24 visits | 
| CSF Biomarkers, Week 24 Visit Value Minus Baseline Value | Changes in cerebrospinal fluid (CSF) concentrations of ceramide, sphingomyelin, citrate, neurofilament protein; brain-derived neurotrophic factor (BDNF), protein carbonyl, Aβ-42 | Between baseline and week 24 visits | 
| Neuroimaging Markers: SV-MRS, Myoinositol, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Single voxel-magnetic resonance spectroscopy (SV-MRS) myoinositol in the basal ganglia. Results were reported as concentrations measured in approximated mmol/L (institutional units). | Changes between baseline and week 24 visits | 
| Neuroimaging Markers: SV-MRS, Myoinositol, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Single voxel-magnetic resonance spectroscopy (SV-MRS) myoinositol in frontal white matter. Results were reported as concentrations measured in approximated mmol/L (institutional units). | Changes between baseline and week 24 visits | 
| Neuroimaging Markers: SV-MRS, Choline, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Single voxel-magnetic resonance spectroscopy (SV-MRS) choline in basal ganglia. Results were reported as concentrations measured in approximated mmol/L (institutional units). | Changes between baseline and week 24 visits | 
| Neuroimaging Markers: SV-MRS, Choline, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Single voxel-magnetic resonance spectroscopy (SV-MRS) choline in frontal white matter. Results were reported as concentrations measured in approximated mmol/L (institutional units). | Changes between baseline and week 24 visits | 
| Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Single voxel-magnetic resonance spectroscopy (SV-MRS) N-acetyl aspartate concentrations in basal ganglia. Results were reported as concentrations measured in approximated mmol/L (institutional units). | Changes between baseline and week 24 visits | 
| Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Single voxel-magnetic resonance spectroscopy (SV-MRS) N-acetyl aspartate concentrations in frontal white matter. Results were reported as concentrations measured in approximated mmol/L (institutional units). | Changes between baseline and week 24 visits | 
| Neuroimaging Markers: DTI, Whole Brain Mean Fractional Anisotropy (FA), Week 24 Visit Value Minus Baseline Value | Diffusion tensor imaging (DTI), change in whole brain fractional anisotropy (FA) between baseline and 24 weeks. FA is a unitless index that is used for measuring diffusion asymmetry. FA values range from 0 to 1 (0 equals no anisotropy; greater anisotropy is indicated by higher FA values approaching the maximum of 1). FA was measured in regions of interest (ROI) automatically generated by the multi-atlas label-fusion method implemented in the MRICloud. Whole brain mean FA = (Sum of (each ROI's FA * volume)) / (Sum of all ROI volumes). | Changes between baseline and week 24 visits | 
| Neuroimaging Markers: Diffusion Weighted Imaging, Whole Brain Mean Diffusivity, Week 24 Visit Value Minus Baseline Value | Diffusion weighted imaging, change in whole brain mean diffusivity (MD) between baseline and 24 weeks. MD was measured as the mean of three eigenvalues and has the unit m^2/s. Higher values indicate greater diffusivity. MD was measured in regions of interest (ROI) automatically generated by the multi-atlas label-fusion method implemented in the MRICloud. Whole brain mean MD = (Sum of (each ROI's MD * volume)) / (Sum of all ROI volumes). | Changes between baseline and week 24 visits | 
| Neuroimaging Markers: ASL, Week 24 Visit Value Minus Baseline Value | Arterial spin labeling (ASL), a novel measure of cerebral blood flow | Changes between baseline and week 24 visits | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-Associated Neurocognitive Disorder (HAND), Intranasal