Clinical trial NCT03081117: Intranasal Insulin for the Treatment of HAND
Official title: Clinical Trial of Intranasal Insulin for the Treatment of HIV-associated Neurocognitive Disorder (HAND)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: HIV Dementia
HIV-Associated Cognitive Motor Complex
Keywords: HIV-Associated Neurocognitive Disorder (HAND)
Intranasal
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
First posted: 2017-03-16
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized double-blind placebo-controlled clinical trial
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Serious Adverse Event Frequency
timeFrame: Total during 24-week trial
measure: Serious Adverse Event Frequency, Participant Count
timeFrame: Total during 24-week trial
measure: Neurocognitive Performance: Global Deficit Score (GDS), Week 24 Visit Score Minus Baseline Score
timeFrame: Difference between baseline and week 24 visits
Secondary outcomes:
measure: Neurocognitive Performance: NPZ-8 Score, Week 24 Visit Score Minus Baseline Score
timeFrame: Difference between baseline and week 24 visits
measure: CSF Biomarkers, Week 24 Visit Value Minus Baseline Value
timeFrame: Between baseline and week 24 visits
measure: Neuroimaging Markers: SV-MRS, Myoinositol, Basal Ganglia, Week 24 Visit Value Minus Baseline Value
timeFrame: Changes between baseline and week 24 visits
measure: Neuroimaging Markers: SV-MRS, Myoinositol, Frontal White Matter, Week 24 Visit Value Minus Baseline Value
timeFrame: Changes between baseline and week 24 visits
measure: Neuroimaging Markers: SV-MRS, Choline, Basal Ganglia, Week 24 Visit Value Minus Baseline Value
timeFrame: Changes between baseline and week 24 visits
measure: Neuroimaging Markers: SV-MRS, Choline, Frontal White Matter, Week 24 Visit Value Minus Baseline Value
timeFrame: Changes between baseline and week 24 visits
measure: Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Basal Ganglia, Week 24 Visit Value Minus Baseline Value
timeFrame: Changes between baseline and week 24 visits
measure: Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Frontal White Matter, Week 24 Visit Value Minus Baseline Value
timeFrame: Changes between baseline and week 24 visits
measure: Neuroimaging Markers: DTI, Whole Brain Mean Fractional Anisotropy (FA), Week 24 Visit Value Minus Baseline Value
timeFrame: Changes between baseline and week 24 visits
measure: Neuroimaging Markers: Diffusion Weighted Imaging, Whole Brain Mean Diffusivity, Week 24 Visit Value Minus Baseline Value
timeFrame: Changes between baseline and week 24 visits
measure: Neuroimaging Markers: ASL, Week 24 Visit Value Minus Baseline Value
timeFrame: Changes between baseline and week 24 visits
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: The Johns Hopkins Institute for Clinical and Translational Research, Adult Outpatient Clinical Research Unit
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Leah Rubin, PhD
role: PRINCIPAL_INVESTIGATOR
References: