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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.
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Insulin, intranasal | Experimental | Regular insulin, 20 IU intranasal twice a day for 24 weeks; 0.2 mL per dose |
|
| Placebo, intranasal | Placebo Comparator | Saline solution (placebo), intranasal twice a day for 24 weeks; 0.2 mL per dose |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Insulin, intranasal | Drug | Regular insulin administered by specialized, non-commercial intranasal drug delivery device |
|
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Leah Rubin, PhD | Johns Hopkins University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Johns Hopkins Institute for Clinical and Translational Research, Adult Outpatient Clinical Research Unit | Baltimore | Maryland | 21287 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Insulin, Intranasal | Regular insulin, 20 IU intranasal twice a day for 24 weeks; 0.2 mL per dose Insulin, intranasal: Regular insulin administered by specialized, non-commercial intranasal drug delivery device |
| FG001 | Placebo, Intranasal | Saline solution (placebo), intranasal twice a day for 24 weeks; 0.2 mL per dose Placebo, intranasal: Saline solution administered by specialized, non-commercial intranasal drug delivery device |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Insulin, Intranasal | Regular insulin, 20 IU intranasal twice a day for 24 weeks; 0.2 mL per dose Insulin, intranasal: Regular insulin administered by specialized, non-commercial intranasal drug delivery device |
| BG001 | Placebo, Intranasal |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Serious Adverse Event Frequency | Number of documented serious adverse events per participant, mean | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Posted | Mean | Standard Deviation | Number of SAEs/participant | Total during 24-week trial |
|
AEs were reported monthly over the 24-week period that each participant was on study or when taken off study if he/she did not complete the trial. Participants who completed the trial were followed up to 4 weeks after taking the last dose of the investigational product. Participants who stopped the intervention early remained on study for continued follow-up, to the extent possible, through study visits, telephone communication, and medical record review for intent-to-treat analysis.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Insulin, Intranasal | Regular insulin, 20 IU intranasal twice a day for 24 weeks; 0.2 mL per dose Insulin, intranasal: Regular insulin administered by specialized, non-commercial intranasal drug delivery device |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Major depressive episode | Psychiatric disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fall | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Leah Rubin, Associate Professor of Neurology, Psychiatry, and Epidemiology | Johns Hopkins University | 410-955-7311 | lrubin@jhu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 16, 2018 | Jun 3, 2021 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| D015526 | AIDS Dementia Complex |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D007328 | Insulin |
| ID | Term |
|---|---|
| D011384 | Proinsulin |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
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Randomized double-blind placebo-controlled clinical trial
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| Placebo, intranasal | Drug | Saline solution administered by specialized, non-commercial intranasal drug delivery device |
|
| 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 |
Saline solution (placebo), intranasal twice a day for 24 weeks; 0.2 mL per dose Placebo, intranasal: Saline solution administered by specialized, non-commercial intranasal drug delivery device |
| BG002 | Total | Total of all reporting groups |
| Median |
| Inter-Quartile Range |
| years |
|
| Age, Customized | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Count of Participants | Participants |
|
| Sex: Female, Male | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Education, Continuous | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | years |
|
| Education, Categorical | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Count of Participants | Participants |
|
| Global Deficit Score (GDS), Baseline | GDS is a composite score of neurocognitive test performance comprised of 14 data points from 9 tests (Hopkins Verbal Learning, Rey Complex Figure, WAIS symbol-digit, grooved pegboard, CalCAP, Trail-making, Stroop Color Interference, timed gait, and FAS verbal fluency). Raw scores were transformed to t-scores using age/education stratified norms, assigned discrete values 0 to 5 (t-score categorization > or =40 is 0, 35.00 to 39.99 =1, 30.00 to 34.99 =2, 25.00 to 29.99 =3, 20.00 to 24.99 =4, and <20 =5) and then averaged. Higher GDS is a worse outcome (0 = no deficits and 5 = maximum deficits). | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | units on a scale |
|
| Beck Depression Inventory II | The Beck Depression Inventory II is a standard 21-item paper questionnaire in which participants self-rated signs and symptoms of depression over the preceding 2 weeks. Each item was scored 0, 1, 2, or 3, and then added up for a total score (test range: 0 - 63) with higher numbers indicating greater severity of depressive symptoms. | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | units on a scale |
|
| Beck Depression Inventory II | The Beck Depression Inventory II is a standard 21-item paper questionnaire in which participants self-rated signs and symptoms of depression over the preceding 2 weeks. Each item was scored 0, 1, 2, or 3, and then added up for a total score (test range: 0 - 63) with higher numbers indicating greater severity of depressive symptoms. | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Median | Inter-Quartile Range | units on a scale |
|
| Estimated IQ, Hopkins Adult Reading Test | The Hopkins Adult Reading Test (HART) is a standard 35 item word list that the participant reads while the tester assesses his/her pronunciation of each word. One point is awarded for each correct pronunciation (raw score range 0-35). The number correct is then transformed to a standard score based on age/education/sex/race matched normative data with the mean set to 100 and standard deviation of 15 (range defined valid between 73 and 131). Higher scores indicate greater word recognition. It serves as an estimated measure of premorbid abilities (i.e. Intelligence Quotient). | Two participants did not perform the Hopkins Adult Reading Test at baseline. Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | units on a scale |
|
| Hopkins Verbal Learning Test, Total (Trials 1-3) | The total sum of correct words immediately recalled over three trials. The raw scores were transformed to Z-scores based on an age-matched reference population. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the reference population with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a greater verbal learning score (better outcome). Z-scores under -3.5 were limited to -3.5. | Measure Analysis Population Description: Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | z-score |
|
| Hopkins Verbal Learning Test, Delayed Recall | Total words recalled after 20 minute delay. The raw scores were transformed to Z-scores based on an age-matched reference population. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the reference population with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a greater verbal learning score (better outcome). Z-scores under -3.5 were limited to -3.5. | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | z-score |
|
| Rey Complex Figure Test, Copy | Standard Rey Complex Figure scoring applied to assess ability to copy the test figure (range 0-36). The raw scores were transformed to Z-scores based on age-matched reference population data. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the reference population with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a greater visual-spatial reconstruction score (better outcome). Z-scores under -3.5 were limited to -3.5. | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | z-score |
|
| Rey Complex Figure Test, Delayed Recall | Standard Rey Complex Figure scoring applied to assess ability to recall the test figure after 20 minutes (range 0-36). The raw scores were transformed to Z-scores based on age-matched reference population data. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the reference population with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a greater visual-spatial recall score (better outcome). Z-scores under -3.5 were limited to -3.5. | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | z-score |
|
| Trail Making Test, Part A | Time to complete Trail Making Test Part A. The raw scores (measured in seconds) were transformed to directionally inverted Z-scores based on age/education/sex-matched reference population data. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the reference population. The inverted Z-scores produce negative numbers when times are higher than the mean and positive values when times are lower. Higher Z-scores indicate a greater motor speed (better outcome). Z-scores under -3.5 were limited to -3.5. | Measure Analysis Population Description: Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | z-score |
|
| Trail Making Test, Part B | Time to complete Trail Making Test Part B. The raw scores (measured in seconds) were transformed to directionally inverted Z-scores based on age/education/sex-matched reference population data. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the reference population. The inverted Z-scores produce negative numbers when times are higher than the mean and positive values when times are lower. Higher Z-scores indicate a greater motor speed (better outcome). Z-scores under -3.5 were limited to -3.5. | Two participants were unable to complete test in the allotted time. Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | z-score |
|
| Grooved Pegboard Test, Dominant Hand | Time to complete grooved pegboard task with dominant hand. The raw scores (measured in seconds) were transformed to directionally inverted Z-scores based on age/education/sex-matched reference population data. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the reference population. The inverted Z-scores produce negative numbers when times are higher than the mean and positive values when times are lower. Higher Z-scores indicate a greater motor speed (better outcome). Z-scores under -3.5 were limited to -3.5. | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | z-score |
|
| Grooved Pegboard Test, Non-Dominant Hand | Time to complete grooved pegboard task with non-dominant hand. The raw scores (measured in seconds) were transformed to directionally inverted Z-scores based on age/education/sex-matched reference population data. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the reference population. The inverted Z-scores produce negative numbers when times are higher than the mean and positive values when times are lower. Higher Z-scores indicate a greater motor speed (better outcome). Z-scores under -3.5 were limited to -3.5. | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | z-score |
|
| CD4, Absolute Count | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | cells per cubic mm |
|
| HIV Viral Load, Plasma | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Count of Participants | Participants |
|
| Body Mass Index (BMI) | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | kg/m^2 |
|
| Glucose, Fasting Blood | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | mg/dL |
|
| Insulin, Fasting Serum | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | mcU/mL |
|
| Amylase, Blood | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | U/L |
|
| Lipase, Blood | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | U/L |
|
| Thyroid Stimulating Hormone | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Mean | Standard Deviation | u[IU]/mL |
|
| Vitamin B12, Blood | Two participants did not have baseline vitamin B12 levels tested. Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Median | Inter-Quartile Range | pg/mL |
|
| Placebo, Intranasal |
Saline solution (placebo), intranasal twice a day for 24 weeks; 0.2 mL per dose Placebo, intranasal: Saline solution administered by specialized, non-commercial intranasal drug delivery device |
|
|
| Primary | Serious Adverse Event Frequency, Participant Count | Number participants with at least one documented serious adverse event, count | Enrolled: All participants started on study intervention. Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Posted | Count of Participants | Participants | Total during 24-week trial |
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| Primary | 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). | Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Posted | Mean | Standard Deviation | units on a scale | Difference between baseline and week 24 visits |
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| Secondary | 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. | Completed Trial (ITT): All participants with both primary outcome measures at 24 weeks. Completed Trial (Per Protocol): Participants with both primary outcome measures at 24 weeks and who demonstrated greater than 16 weeks adherence to the study intervention. | Posted | Mean | Standard Deviation | z-score | Difference between baseline and week 24 visits |
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| Secondary | 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 | Baseline and Week 24 CSF samples were collected from only 4 participants. CSF biomarker assays were not performed because the target number of 36 evaluable patients was not reached, and we had insufficient power to detect a true difference in change per the statistical analysis plan. | Posted | Between baseline and week 24 visits |
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| Secondary | 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). | MRS was performed at both baseline and 24 Weeks on 16 participants (Pts). However, one had invalid basal ganglia MRS results at Week 24, another is missing all Week 24 MRS results due to technical error in data collection. Available MRS (data for outcome measure): 14 Pts. (Note: one of the Pts did not complete trial, two were Intent-to-Treat) Completed Trial (Per Protocol) with available MRS data: 11 Pts. | Posted | Mean | Standard Deviation | mmol/L, approx. (institutional units) | Changes between baseline and week 24 visits |
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| Secondary | 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). | MRS was performed at both baseline and 24 Weeks on 16 participants (Pts). However, three Pts had invalid frontal white matter MRS results at either baseline or Week 24, and a fourth is missing all Week 24 MRS results due to technical error in data collection. Available MRS (data for outcome measure): 12 Pts. (Note: one of the Pts did not complete trial, two were Intent-to-Treat) Completed Trial (Per Protocol) with available MRS data: 9 Pts | Posted | Mean | Standard Deviation | mmol/L, approx. (institutional units) | Changes between baseline and week 24 visits |
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| Secondary | 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). | MRS was performed at both baseline and 24 Weeks on 16 participants (Pts). However, one had invalid basal ganglia MRS results at Week 24, another is missing all Week 24 MRS results due to technical error in data collection. Available MRS (data for outcome measure): 14 Pts. (Note: one of the Pts did not complete trial, two were Intent-to-Treat) Completed Trial (Per Protocol) with available MRS data: 11 Pts | Posted | Mean | Standard Deviation | mmol/L, approx. (institutional units) | Changes between baseline and week 24 visits |
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| Secondary | 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). | MRS was performed at both baseline and 24 Weeks on 16 participants (Pts). However, three Pts had invalid frontal white matter MRS results at either baseline or Week 24, and a fourth is missing all Week 24 MRS results due to technical error in data collection. Available MRS (data for outcome measure): 12 Pts. (Note: one of the Pts did not complete trial, two were Intent-to-Treat) Completed Trial (Per Protocol) with available MRS data: 9 Pts | Posted | Mean | Standard Deviation | mmol/L, approx. (institutional units) | Changes between baseline and week 24 visits |
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| Secondary | 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). | MRS was performed at both baseline and 24 Weeks on 16 participants (Pts). However, one had invalid basal ganglia MRS results at Week 24, another is missing all Week 24 MRS results due to technical error in data collection. Available MRS (data for outcome measure): 14 Pts. (Note: one of the Pts did not complete trial, two were Intent-to-Treat) Completed Trial (Per Protocol) with available MRS data: 11 Pts | Posted | Mean | Standard Deviation | mmol/L, approx. (institutional units) | Changes between baseline and week 24 visits |
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| Secondary | 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). | MRS was performed at both baseline and 24 Weeks on 16 participants (Pts). However, three Pts had invalid frontal white matter MRS results at either baseline or Week 24, and a fourth is missing all Week 24 MRS results due to technical error in data collection. Available MRS (data for outcome measure): 12 Pts. (Note: one of the Pts did not complete trial, two were Intent-to-Treat) Completed Trial (Per Protocol) with available MRS data: 9 Pts | Posted | Mean | Standard Deviation | mmol/L, approx. (institutional units) | Changes between baseline and week 24 visits |
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| Secondary | 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). | MRS was performed at both baseline and 24 Weeks on 16 participants (Pts). However, one is missing all Week 24 DTI results due to technical error in data collection. Available MRS (data for outcome measure): 15 Pts. (Note: one of the Pts did not complete trial, two were Intent-to-Treat) Completed Trial (Per Protocol) with available MRS data: 12 Pts | Posted | Mean | Standard Deviation | index | Changes between baseline and week 24 visits |
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| Secondary | 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). | MRS was performed at both baseline and 24 Weeks on 16 participants (Pts). However, one is missing all Week 24 DTI results due to technical error in data collection. Available MRS (data for outcome measure): 15 Pts. (Note: one of the Pts did not complete trial, two were Intent-to-Treat) Completed Trial (Per Protocol) with available MRS data: 12 Pts | Posted | Mean | Standard Deviation | m^2/s | Changes between baseline and week 24 visits |
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| Secondary | Neuroimaging Markers: ASL, Week 24 Visit Value Minus Baseline Value | Arterial spin labeling (ASL), a novel measure of cerebral blood flow | Collected data were not considered valid due to an equipment malfunction. | Posted | Changes between baseline and week 24 visits |
|
|
| 0 |
| 10 |
| 2 |
| 10 |
| 10 |
| 10 |
| EG001 | Placebo, Intranasal | Saline solution (placebo), intranasal twice a day for 24 weeks; 0.2 mL per dose Placebo, intranasal: Saline solution administered by specialized, non-commercial intranasal drug delivery device | 0 | 11 | 2 | 11 | 11 | 11 |
| Kidney obstruction | Renal and urinary disorders | Systematic Assessment |
|
| Cardiac event | Cardiac disorders | Systematic Assessment |
|
| Hospitalization for syncope/hypotension | Vascular disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Nosebleed | General disorders | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Congestion/Runny Nose | General disorders | Systematic Assessment |
|
| Nasal Irritation or Reaction (during administration of investigational product) | General disorders | Systematic Assessment |
|
| Upper Respiratory Infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Odor/Taste (during administration of investigational product) | Product Issues | Systematic Assessment |
|
| Accidental Injury | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Upper Gastrointestinal Pain or Discomfort | Gastrointestinal disorders | Systematic Assessment |
|
| Infection (other than upper respiratory infection) | Infections and infestations | Systematic Assessment |
|
| Creatinine, High Blood | Renal and urinary disorders | Systematic Assessment |
|
| Nausea | General disorders | Systematic Assessment |
|
| Dizziness | General disorders | Systematic Assessment |
|
| Blood Pressure, High (acute) | General disorders | Systematic Assessment |
|
| Edema, Lower Extremity | General disorders | Systematic Assessment |
|
| Glucose, High Blood | Endocrine disorders | Systematic Assessment |
|
| Amylase, High Blood | Endocrine disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D015229 |
| Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D006728 |
| Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| 50-59 |
|
| 60-69 |
|
| 40-49 |
|
| 50-59 |
|
| 60-69 |
|
| 40-49 |
|
| 50-59 |
|
| 60-69 |
|
| Male |
|
| Male |
|
| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Some College or Associates Degree |
|
| College Degree |
|
| High School Diploma |
|
| Some College or Associates Degree |
|
| College Degree |
|
| High School Diploma |
|
| Some College or Associates Degree |
|
| College Degree |
|
| Low Detectable (50-99 copies/mL) |
|
| Low Detectable (20-49 copies/mL) |
|
| Low Detectable (50-99 copies/mL) |
|
| Low Detectable (20-49 copies/mL) |
|
| Low Detectable (50-99 copies/mL) |
|
| Completed Trial (ITT) |
|
|
| Completed Trial (Per Protocol) |
|
|
| Completed Trial (Per Protocol) |
|
|
Analysis for Per Protocol group. |
| t-test, 2 sided |
Degrees of freedom = 12 |
| 0.0103 |
The threshold for statistical significance was p = 0.05. |
| Mean Difference (Net) |
| -0.5146 |
| 2-Sided |
| Superiority |
| Completed Trial (Per Protocol) |
|
|
| Completed Trial (Per Protocol) |
|
|
| Completed Trial (Per Protocol) |
|
|
| Completed Trial (Per Protocol) |
|
|
| Completed Trial (Per Protocol) |
|
|
| Completed Trial (Per Protocol) |
|
|
| Completed Trial (Per Protocol) |
|
|
| Per Protocol |
|
|
Analysis for Per Protocol group. |
| t-test, 2 sided |
Degrees fo freedom = 10 |
| 0.505 |
The threshold for statistical significance was p = 0.05. |
| Mean Difference (Net) |
| 0.0025586 |
| 2-Sided |
| Superiority |
| Per Protocol |
|
|
Analysis for Per Protocol group. |
| t-test, 2 sided |
Degrees of freedom = 10 |
| 0.86 |
The threshold for statistical significance was p = 0.05. |
| Mean Difference (Net) |
| -0.0000054 |
| 2-Sided |
| Superiority |