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Intranasal Insulin for the Treatment of HAND

Primary Purpose

HIV Dementia, HIV-Associated Cognitive Motor Complex

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Insulin, intranasal

Placebo, intranasal

About this trial

This is an interventional treatment trial for HIV Dementia focused on measuring HIV-Associated Neurocognitive Disorder (HAND), Intranasal

Eligibility Criteria

18 Years - 69 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

The Johns Hopkins Institute for Clinical and Translational Research, Adult Outpatient Clinical Research Unit

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Insulin, intranasal

Placebo, intranasal

Arm Description

Regular insulin, 20 IU intranasal twice a day for 24 weeks; 0.2 mL per dose

Saline solution (placebo), intranasal twice a day for 24 weeks; 0.2 mL per dose

Outcomes

Primary Outcome Measures

Serious Adverse Event Frequency

Number of documented serious adverse events per participant, mean

Serious Adverse Event Frequency, Participant Count

Number participants with at least one documented serious adverse event, count

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).

Secondary Outcome Measures

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.

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

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).

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).

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).

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).

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).

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).

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).

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).

Neuroimaging Markers: ASL, Week 24 Visit Value Minus Baseline Value

Arterial spin labeling (ASL), a novel measure of cerebral blood flow

Full Information

NCT ID

NCT03081117

First Posted

March 9, 2017

Last Updated

June 15, 2021

Sponsor

Johns Hopkins University

1. Study Identification

Unique Protocol Identification Number

NCT03081117

Brief Title

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

2. Study Status

Record Verification Date

June 2021

Overall Recruitment Status

Terminated

Why Stopped

On 3/15/2020 study visits were suspended due to COVID-19 pandemic. With safety concerns surrounding COVID-19 and difficulty recruiting, the investigators decided to close enrollment 10/16/2020 after interim data were reviewed by the DSMB and NIH.

Study Start Date

August 1, 2017 (Actual)

Primary Completion Date

May 20, 2020 (Actual)

Study Completion Date

October 16, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Johns Hopkins University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Dementia, HIV-Associated Cognitive Motor Complex

Keywords

HIV-Associated Neurocognitive Disorder (HAND), Intranasal

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Randomized double-blind placebo-controlled clinical trial

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Insulin, intranasal

Arm Type

Experimental

Arm Description

Regular insulin, 20 IU intranasal twice a day for 24 weeks; 0.2 mL per dose

Arm Title

Placebo, intranasal

Arm Type

Placebo Comparator

Arm Description

Saline solution (placebo), intranasal twice a day for 24 weeks; 0.2 mL per dose

Intervention Type

Drug

Intervention Name(s)

Insulin, intranasal

Other Intervention Name(s)

Novolin R

Intervention Description

Regular insulin administered by specialized, non-commercial intranasal drug delivery device

Intervention Type

Drug

Intervention Name(s)

Placebo, intranasal

Intervention Description

Saline solution administered by specialized, non-commercial intranasal drug delivery device

Primary Outcome Measure Information:

Title

Serious Adverse Event Frequency

Description

Number of documented serious adverse events per participant, mean

Time Frame

Total during 24-week trial

Title

Serious Adverse Event Frequency, Participant Count

Description

Number participants with at least one documented serious adverse event, count

Time Frame

Total during 24-week trial

Title

Neurocognitive Performance: Global Deficit Score (GDS), Week 24 Visit Score Minus Baseline Score

Description

Time Frame

Difference between baseline and week 24 visits

Secondary Outcome Measure Information:

Title

Neurocognitive Performance: NPZ-8 Score, Week 24 Visit Score Minus Baseline Score

Description

Time Frame

Difference between baseline and week 24 visits

Title

CSF Biomarkers, Week 24 Visit Value Minus Baseline Value

Description

Changes in cerebrospinal fluid (CSF) concentrations of ceramide, sphingomyelin, citrate, neurofilament protein; brain-derived neurotrophic factor (BDNF), protein carbonyl, Aβ-42

Time Frame

Between baseline and week 24 visits

Title

Neuroimaging Markers: SV-MRS, Myoinositol, Basal Ganglia, Week 24 Visit Value Minus Baseline Value

Description

Single voxel-magnetic resonance spectroscopy (SV-MRS) myoinositol in the basal ganglia. Results were reported as concentrations measured in approximated mmol/L (institutional units).

Time Frame