HIV-Associated Cognitive Motor Complex, HIV Dementia
Conditions
Keywords
HIV-Associated Neurocognitive Disorder (HAND), Intranasal
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.
Interventions
DRUGInsulin, intranasal
Regular insulin administered by specialized, non-commercial intranasal drug delivery device
Saline solution administered by specialized, non-commercial intranasal drug delivery device
Sponsors
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized double-blind placebo-controlled clinical trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serious Adverse Event Frequency | Total during 24-week trial | Number of documented serious adverse events per participant, mean |
| Serious Adverse Event Frequency, Participant Count | Total during 24-week trial | Number participants with at least one documented serious adverse event, count |
| Neurocognitive Performance: Global Deficit Score (GDS), Week 24 Visit Score Minus Baseline Score | Difference between baseline and week 24 visits | 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
| Measure | Time frame | Description |
|---|---|---|
| Neuroimaging Markers: SV-MRS, Myoinositol, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Changes between baseline and week 24 visits | 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 | Changes between baseline and week 24 visits | 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 | Changes between baseline and week 24 visits | 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 | Changes between baseline and week 24 visits | 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). |
| Neurocognitive Performance: NPZ-8 Score, Week 24 Visit Score Minus Baseline Score | Difference between baseline and week 24 visits | 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. |
| Neuroimaging Markers: DTI, Whole Brain Mean Fractional Anisotropy (FA), Week 24 Visit Value Minus Baseline Value | Changes between baseline and week 24 visits | 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 | Changes between baseline and week 24 visits | 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 | Changes between baseline and week 24 visits | Arterial spin labeling (ASL), a novel measure of cerebral blood flow |
| Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Changes between baseline and week 24 visits | 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). |
| CSF Biomarkers, Week 24 Visit Value Minus Baseline Value | Between baseline and week 24 visits | 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 | Changes between baseline and week 24 visits | Single voxel-magnetic resonance spectroscopy (SV-MRS) myoinositol in the basal ganglia. Results were reported as concentrations measured in approximated mmol/L (institutional units). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 10 |
| 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 | 11 |
| Total | 21 |
Baseline characteristics
| Characteristic | Insulin, Intranasal | Placebo, Intranasal | Total |
|---|---|---|---|
| Age, Continuous Completed Trial (ITT) | 57 years | 58 years | 57.5 years |
| Age, Continuous Completed Trial (Per Protocol) | 56 years | 57.5 years | 57 years |
| Age, Continuous Enrolled | 58.5 years | 58 years | 58 years |
| Age, Customized Completed Trial (ITT) 30-39 | 1 Participants | 0 Participants | 1 Participants |
| Age, Customized Completed Trial (ITT) 40-49 | 0 Participants | 1 Participants | 1 Participants |
| Age, Customized Completed Trial (ITT) 50-59 | 4 Participants | 5 Participants | 9 Participants |
| Age, Customized Completed Trial (ITT) 60-69 | 2 Participants | 3 Participants | 5 Participants |
| Age, Customized Completed Trial (Per Protocol) 30-39 | 1 Participants | 0 Participants | 1 Participants |
| Age, Customized Completed Trial (Per Protocol) 40-49 | 0 Participants | 1 Participants | 1 Participants |
| Age, Customized Completed Trial (Per Protocol) 50-59 | 4 Participants | 5 Participants | 9 Participants |
| Age, Customized Completed Trial (Per Protocol) 60-69 | 1 Participants | 2 Participants | 3 Participants |
| Age, Customized Enrolled 30-39 | 1 Participants | 0 Participants | 1 Participants |
| Age, Customized Enrolled 40-49 | 0 Participants | 1 Participants | 1 Participants |
| Age, Customized Enrolled 50-59 | 5 Participants | 5 Participants | 10 Participants |
| Age, Customized Enrolled 60-69 | 4 Participants | 5 Participants | 9 Participants |
| Amylase, Blood Completed Trial (ITT) | 89.14 U/L STANDARD_DEVIATION 35.43 | 80.11 U/L STANDARD_DEVIATION 30.51 | 84.06 U/L STANDARD_DEVIATION 31.93 |
| Amylase, Blood Completed Trial (Per Protocol) | 88.83 U/L STANDARD_DEVIATION 38.8 | 82.50 U/L STANDARD_DEVIATION 31.7 | 85.21 U/L STANDARD_DEVIATION 33.63 |
| Amylase, Blood Enrolled | 89.00 U/L STANDARD_DEVIATION 30.32 | 78.73 U/L STANDARD_DEVIATION 27.53 | 83.62 U/L STANDARD_DEVIATION 28.64 |
| Beck Depression Inventory II Completed Trial (ITT) | 13.0 units on a scale | 4.0 units on a scale | 5.0 units on a scale |
| Beck Depression Inventory II Completed Trial (Per Protocol) | 13.5 units on a scale | 5.88 units on a scale STANDARD_DEVIATION 4.67 | 7.93 units on a scale STANDARD_DEVIATION 6.22 |
| Beck Depression Inventory II Enrolled | 11.0 units on a scale | 5.55 units on a scale STANDARD_DEVIATION 4.08 | 7.71 units on a scale STANDARD_DEVIATION 6.5 |
| Body Mass Index (BMI) Completed Trial (ITT) | 31.13 kg/m^2 STANDARD_DEVIATION 9.6 | 30.24 kg/m^2 STANDARD_DEVIATION 5.73 | 30.63 kg/m^2 STANDARD_DEVIATION 7.39 |
| Body Mass Index (BMI) Completed Trial (Per Protocol) | 32.38 kg/m^2 STANDARD_DEVIATION 9.86 | 30.44 kg/m^2 STANDARD_DEVIATION 6.1 | 31.27 kg/m^2 STANDARD_DEVIATION 7.64 |
| Body Mass Index (BMI) Enrolled | 31.33 kg/m^2 STANDARD_DEVIATION 8.38 | 31.45 kg/m^2 STANDARD_DEVIATION 6.83 | 31.40 kg/m^2 STANDARD_DEVIATION 7.41 |
| CD4, Absolute Count Completed Trial (ITT) | 538.86 cells per cubic mm STANDARD_DEVIATION 127.73 | 527.78 cells per cubic mm STANDARD_DEVIATION 176.3 | 532.63 cells per cubic mm STANDARD_DEVIATION 152.1 |
| CD4, Absolute Count Completed Trial (Per Protocol) | 518.17 cells per cubic mm STANDARD_DEVIATION 126.42 | 514.63 cells per cubic mm STANDARD_DEVIATION 183.69 | 516.14 cells per cubic mm STANDARD_DEVIATION 155.95 |
| CD4, Absolute Count Enrolled | 616.80 cells per cubic mm STANDARD_DEVIATION 170.18 | 598.55 cells per cubic mm STANDARD_DEVIATION 290.86 | 607.24 cells per cubic mm STANDARD_DEVIATION 235.41 |
| Education, Categorical Completed Trial (ITT) 9th to 11th Grade | 1 Participants | 2 Participants | 3 Participants |
| Education, Categorical Completed Trial (ITT) College Degree | 1 Participants | 1 Participants | 2 Participants |
| Education, Categorical Completed Trial (ITT) High School Diploma | 3 Participants | 5 Participants | 8 Participants |
| Education, Categorical Completed Trial (ITT) Some College or Associates Degree | 2 Participants | 1 Participants | 3 Participants |
| Education, Categorical Completed Trial (Per Protocol) 9th to 11th Grade | 1 Participants | 1 Participants | 2 Participants |
| Education, Categorical Completed Trial (Per Protocol) College Degree | 0 Participants | 1 Participants | 1 Participants |
| Education, Categorical Completed Trial (Per Protocol) High School Diploma | 3 Participants | 5 Participants | 8 Participants |
| Education, Categorical Completed Trial (Per Protocol) Some College or Associates Degree | 2 Participants | 1 Participants | 3 Participants |
| Education, Categorical Enrolled 9th to 11th Grade | 2 Participants | 3 Participants | 5 Participants |
| Education, Categorical Enrolled College Degree | 1 Participants | 1 Participants | 2 Participants |
| Education, Categorical Enrolled High School Diploma | 4 Participants | 6 Participants | 10 Participants |
| Education, Categorical Enrolled Some College or Associates Degree | 3 Participants | 1 Participants | 4 Participants |
| Education, Continuous Completed Trial (ITT) | 12.86 years STANDARD_DEVIATION 2.34 | 12.33 years STANDARD_DEVIATION 1.94 | 12.56 years STANDARD_DEVIATION 2.06 |
| Education, Continuous Completed Trial (Per Protocol) | 12.33 years STANDARD_DEVIATION 2.07 | 12.50 years STANDARD_DEVIATION 2 | 12.43 years STANDARD_DEVIATION 1.95 |
| Education, Continuous Enrolled | 12.70 years STANDARD_DEVIATION 2.06 | 12.09 years STANDARD_DEVIATION 1.87 | 12.38 years STANDARD_DEVIATION 1.94 |
| Estimated IQ, Hopkins Adult Reading Test Completed Trial (ITT) | 98.67 units on a scale STANDARD_DEVIATION 6.5 | 97.67 units on a scale STANDARD_DEVIATION 12.22 | 98.07 units on a scale STANDARD_DEVIATION 10.03 |
| Estimated IQ, Hopkins Adult Reading Test Completed Trial (Per Protocol) | 98.80 units on a scale STANDARD_DEVIATION 7.26 | 98.63 units on a scale STANDARD_DEVIATION 12.69 | 98.69 units on a scale STANDARD_DEVIATION 10.56 |
| Estimated IQ, Hopkins Adult Reading Test Enrolled | 97.13 units on a scale STANDARD_DEVIATION 6.64 | 96.00 units on a scale STANDARD_DEVIATION 11.54 | 96.47 units on a scale STANDARD_DEVIATION 9.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 11 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Global Deficit Score (GDS), Baseline Completed Trial (ITT) | 1.31 units on a scale STANDARD_DEVIATION 0.56 | 0.75 units on a scale STANDARD_DEVIATION 0.47 | 1.00 units on a scale STANDARD_DEVIATION 0.57 |
| Global Deficit Score (GDS), Baseline Completed Trial (Per Protocol) | 1.22 units on a scale STANDARD_DEVIATION 0.55 | 0.77 units on a scale STANDARD_DEVIATION 0.5 | 0.97 units on a scale STANDARD_DEVIATION 0.55 |
| Global Deficit Score (GDS), Baseline Enrolled | 1.37 units on a scale STANDARD_DEVIATION 0.74 | 0.85 units on a scale STANDARD_DEVIATION 0.57 | 1.10 units on a scale STANDARD_DEVIATION 0.7 |
| Glucose, Fasting Blood Completed Trial (ITT) | 101.86 mg/dL STANDARD_DEVIATION 13.69 | 93.33 mg/dL STANDARD_DEVIATION 12.35 | 97.06 mg/dL STANDARD_DEVIATION 13.24 |
| Glucose, Fasting Blood Completed Trial (Per Protocol) | 101.83 mg/dL STANDARD_DEVIATION 15 | 95.63 mg/dL STANDARD_DEVIATION 10.97 | 98.29 mg/dL STANDARD_DEVIATION 12.71 |
| Glucose, Fasting Blood Enrolled | 101.50 mg/dL STANDARD_DEVIATION 11.68 | 93.55 mg/dL STANDARD_DEVIATION 11.11 | 97.33 mg/dL STANDARD_DEVIATION 11.82 |
| Grooved Pegboard Test, Dominant Hand Completed Trial (ITT) | -0.74 z-score STANDARD_DEVIATION 0.97 | -0.83 z-score STANDARD_DEVIATION 0.5 | -0.79 z-score STANDARD_DEVIATION 0.72 |
| Grooved Pegboard Test, Dominant Hand Completed Trial (Per Protocol) | -0.68 z-score STANDARD_DEVIATION 1.05 | -0.90 z-score STANDARD_DEVIATION 0.5 | -0.81 z-score STANDARD_DEVIATION 0.75 |
| Grooved Pegboard Test, Dominant Hand Enrolled | -0.83 z-score STANDARD_DEVIATION 1.09 | -0.78 z-score STANDARD_DEVIATION 0.49 | -0.80 z-score STANDARD_DEVIATION 0.81 |
| Grooved Pegboard Test, Non-Dominant Hand Completed Trial (ITT) | -1.41 z-score STANDARD_DEVIATION 1.05 | -0.38 z-score STANDARD_DEVIATION 1.56 | -0.83 z-score STANDARD_DEVIATION 1.42 |
| Grooved Pegboard Test, Non-Dominant Hand Completed Trial (Per Protocol) | -1.27 z-score STANDARD_DEVIATION 1.07 | -0.76 z-score STANDARD_DEVIATION 1.11 | -0.98 z-score STANDARD_DEVIATION 1.08 |
| Grooved Pegboard Test, Non-Dominant Hand Enrolled | -1.42 z-score STANDARD_DEVIATION 1.07 | -0.35 z-score STANDARD_DEVIATION 1.46 | -0.86 z-score STANDARD_DEVIATION 1.37 |
| HIV Viral Load, Plasma Completed Trial (ITT) Low Detectable (20-49 copies/mL) | 4 Participants | 1 Participants | 5 Participants |
| HIV Viral Load, Plasma Completed Trial (ITT) Low Detectable (50-99 copies/mL) | 0 Participants | 1 Participants | 1 Participants |
| HIV Viral Load, Plasma Completed Trial (ITT) Undetectable (<20 copies/mL) | 3 Participants | 7 Participants | 10 Participants |
| HIV Viral Load, Plasma Completed Trial (Per Protocol) Low Detectable (20-49 copies/mL) | 4 Participants | 1 Participants | 5 Participants |
| HIV Viral Load, Plasma Completed Trial (Per Protocol) Low Detectable (50-99 copies/mL) | 0 Participants | 1 Participants | 1 Participants |
| HIV Viral Load, Plasma Completed Trial (Per Protocol) Undetectable (<20 copies/mL) | 2 Participants | 6 Participants | 8 Participants |
| HIV Viral Load, Plasma Enrolled Low Detectable (20-49 copies/mL) | 5 Participants | 1 Participants | 6 Participants |
| HIV Viral Load, Plasma Enrolled Low Detectable (50-99 copies/mL) | 0 Participants | 1 Participants | 1 Participants |
| HIV Viral Load, Plasma Enrolled Undetectable (<20 copies/mL) | 5 Participants | 9 Participants | 14 Participants |
| Hopkins Verbal Learning Test, Delayed Recall Completed Trial (ITT) | -2.10 z-score STANDARD_DEVIATION 1.74 | -0.93 z-score STANDARD_DEVIATION 0.67 | -1.44 z-score STANDARD_DEVIATION 1.34 |
| Hopkins Verbal Learning Test, Delayed Recall Completed Trial (Per Protocol) | -1.89 z-score STANDARD_DEVIATION 1.8 | -0.88 z-score STANDARD_DEVIATION 0.7 | -1.31 z-score STANDARD_DEVIATION 1.33 |
| Hopkins Verbal Learning Test, Delayed Recall Enrolled | -2.00 z-score STANDARD_DEVIATION 1.5 | -1.20 z-score STANDARD_DEVIATION 0.98 | -1.58 z-score STANDARD_DEVIATION 1.29 |
| Hopkins Verbal Learning Test, Total (Trials 1-3) Completed Trial (ITT) | -1.56 z-score STANDARD_DEVIATION 1.15 | -1.01 z-score STANDARD_DEVIATION 0.91 | -1.25 z-score STANDARD_DEVIATION 1.02 |
| Hopkins Verbal Learning Test, Total (Trials 1-3) Completed Trial (Per Protocol) | -1.34 z-score STANDARD_DEVIATION 1.09 | -0.84 z-score STANDARD_DEVIATION 0.8 | -1.06 z-score STANDARD_DEVIATION 0.93 |
| Hopkins Verbal Learning Test, Total (Trials 1-3) Enrolled | -1.41 z-score STANDARD_DEVIATION 1 | -0.96 z-score STANDARD_DEVIATION 0.82 | -1.18 z-score STANDARD_DEVIATION 0.92 |
| Insulin, Fasting Serum Completed Trial (ITT) | 25.23 mcU/mL STANDARD_DEVIATION 38.18 | 19.30 mcU/mL STANDARD_DEVIATION 17.43 | 21.89 mcU/mL STANDARD_DEVIATION 27.47 |
| Insulin, Fasting Serum Completed Trial (Per Protocol) | 28.77 mcU/mL STANDARD_DEVIATION 40.55 | 19.83 mcU/mL STANDARD_DEVIATION 18.56 | 23.66 mcU/mL STANDARD_DEVIATION 28.96 |
| Insulin, Fasting Serum Enrolled | 29.38 mcU/mL STANDARD_DEVIATION 31.93 | 42.66 mcU/mL STANDARD_DEVIATION 82.28 | 36.34 mcU/mL STANDARD_DEVIATION 62.37 |
| Lipase, Blood Completed Trial (ITT) | 22.14 U/L STANDARD_DEVIATION 8.53 | 27.44 U/L STANDARD_DEVIATION 13.9 | 25.13 U/L STANDARD_DEVIATION 11.81 |
| Lipase, Blood Completed Trial (Per Protocol) | 23.67 U/L STANDARD_DEVIATION 8.24 | 26.13 U/L STANDARD_DEVIATION 14.25 | 25.07 U/L STANDARD_DEVIATION 11.7 |
| Lipase, Blood Enrolled | 25.70 U/L STANDARD_DEVIATION 9.7 | 28.55 U/L STANDARD_DEVIATION 12.68 | 27.19 U/L STANDARD_DEVIATION 11.17 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 10 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 10 participants | 11 participants | 21 participants |
| Rey Complex Figure Test, Copy Completed Trial (ITT) | -2.39 z-score STANDARD_DEVIATION 1.25 | -1.12 z-score STANDARD_DEVIATION 1.27 | -1.67 z-score STANDARD_DEVIATION 1.38 |
| Rey Complex Figure Test, Copy Completed Trial (Per Protocol) | -2.20 z-score STANDARD_DEVIATION 1.26 | -0.91 z-score STANDARD_DEVIATION 1.2 | -1.47 z-score STANDARD_DEVIATION 1.35 |
| Rey Complex Figure Test, Copy Enrolled | -2.20 z-score STANDARD_DEVIATION 1.32 | -1.15 z-score STANDARD_DEVIATION 1.14 | -1.65 z-score STANDARD_DEVIATION 1.31 |
| Rey Complex Figure Test, Delayed Recall Completed Trial (ITT) | -0.63 z-score STANDARD_DEVIATION 0.92 | -0.27 z-score STANDARD_DEVIATION 0.9 | -0.43 z-score STANDARD_DEVIATION 0.9 |
| Rey Complex Figure Test, Delayed Recall Completed Trial (Per Protocol) | -0.46 z-score STANDARD_DEVIATION 0.87 | -0.19 z-score STANDARD_DEVIATION 0.93 | -0.31 z-score STANDARD_DEVIATION 0.88 |
| Rey Complex Figure Test, Delayed Recall Enrolled | -0.87 z-score STANDARD_DEVIATION 0.95 | -0.46 z-score STANDARD_DEVIATION 0.91 | -0.65 z-score STANDARD_DEVIATION 0.93 |
| Sex: Female, Male Completed Trial (ITT) Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Completed Trial (ITT) Male | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Completed Trial (Per Protocol) Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Completed Trial (Per Protocol) Male | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Enrolled Female | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Enrolled Male | 7 Participants | 6 Participants | 13 Participants |
| Thyroid Stimulating Hormone Completed Trial (ITT) | 1.52 u[IU]/mL STANDARD_DEVIATION 0.19 | 1.69 u[IU]/mL STANDARD_DEVIATION 0.73 | 1.62 u[IU]/mL STANDARD_DEVIATION 0.55 |
| Thyroid Stimulating Hormone Completed Trial (Per Protocol) | 1.50 u[IU]/mL STANDARD_DEVIATION 0.2 | 1.72 u[IU]/mL STANDARD_DEVIATION 0.77 | 1.63 u[IU]/mL STANDARD_DEVIATION 0.59 |
| Thyroid Stimulating Hormone Enrolled | 1.67 u[IU]/mL STANDARD_DEVIATION 0.34 | 1.50 u[IU]/mL STANDARD_DEVIATION 0.78 | 1.58 u[IU]/mL STANDARD_DEVIATION 0.6 |
| Trail Making Test, Part A Completed Trial (ITT) | -0.91 z-score STANDARD_DEVIATION 0.48 | 0.02 z-score STANDARD_DEVIATION 0.76 | -0.39 z-score STANDARD_DEVIATION 0.79 |
| Trail Making Test, Part A Completed Trial (Per Protocol) | -0.88 z-score STANDARD_DEVIATION 0.52 | -0.16 z-score STANDARD_DEVIATION 0.56 | -0.47 z-score STANDARD_DEVIATION 0.64 |
| Trail Making Test, Part A Enrolled | -0.94 z-score STANDARD_DEVIATION 0.61 | -0.02 z-score STANDARD_DEVIATION 0.72 | -0.46 z-score STANDARD_DEVIATION 0.81 |
| Trail Making Test, Part B Completed Trial (ITT) | -0.66 z-score STANDARD_DEVIATION 0.62 | -0.14 z-score STANDARD_DEVIATION 0.62 | -0.37 z-score STANDARD_DEVIATION 0.65 |
| Trail Making Test, Part B Completed Trial (Per Protocol) | -0.63 z-score STANDARD_DEVIATION 0.67 | -0.13 z-score STANDARD_DEVIATION 0.66 | -0.34 z-score STANDARD_DEVIATION 0.69 |
| Trail Making Test, Part B Enrolled | -0.76 z-score STANDARD_DEVIATION 0.59 | -0.23 z-score STANDARD_DEVIATION 0.64 | -0.48 z-score STANDARD_DEVIATION 0.66 |
| Vitamin B12, Blood Completed Trial (ITT) | 397.0 pg/mL | 461.0 pg/mL | 448.0 pg/mL |
| Vitamin B12, Blood Completed Trial (Per Protocol) | 390.5 pg/mL | 474.0 pg/mL | 448.0 pg/mL |
| Vitamin B12, Blood Enrolled | 390.5 pg/mL | 448.0 pg/mL | 442.0 pg/mL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 11 |
| other Total, other adverse events | 10 / 10 | 11 / 11 |
| serious Total, serious adverse events | 2 / 10 | 2 / 11 |
Outcome results
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).
Time frame: Difference between baseline and week 24 visits
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin, Intranasal | Neurocognitive Performance: Global Deficit Score (GDS), Week 24 Visit Score Minus Baseline Score | Completed Trial (ITT) | -0.1614 units on a scale | Standard Deviation 0.381 |
| Insulin, Intranasal | Neurocognitive Performance: Global Deficit Score (GDS), Week 24 Visit Score Minus Baseline Score | Completed Trial (Per Protocol) | -0.2383 units on a scale | Standard Deviation 0.3529 |
| Placebo, Intranasal | Neurocognitive Performance: Global Deficit Score (GDS), Week 24 Visit Score Minus Baseline Score | Completed Trial (ITT) | 0.2300 units on a scale | Standard Deviation 0.2981 |
| Placebo, Intranasal | Neurocognitive Performance: Global Deficit Score (GDS), Week 24 Visit Score Minus Baseline Score | Completed Trial (Per Protocol) | 0.2763 units on a scale | Standard Deviation 0.282 |
Comparison: Analysis for Intent-to-Treat group.p-value: 0.0366t-test, 2 sided
Comparison: Analysis for Per Protocol group.p-value: 0.0103t-test, 2 sided
Primary
Serious Adverse Event Frequency
Number of documented serious adverse events per participant, mean
Time frame: Total during 24-week trial
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin, Intranasal | Serious Adverse Event Frequency | Enrolled | 0.30 Number of SAEs/participant | Standard Deviation 0.67 |
| Insulin, Intranasal | Serious Adverse Event Frequency | Completed Trial (ITT) | 0.14 Number of SAEs/participant | Standard Deviation 0.38 |
| Insulin, Intranasal | Serious Adverse Event Frequency | Completed Trial (Per Protocol) | 0.00 Number of SAEs/participant | Standard Deviation 0 |
| Placebo, Intranasal | Serious Adverse Event Frequency | Enrolled | 0.18 Number of SAEs/participant | Standard Deviation 0.4 |
| Placebo, Intranasal | Serious Adverse Event Frequency | Completed Trial (ITT) | 0.22 Number of SAEs/participant | Standard Deviation 0.44 |
| Placebo, Intranasal | Serious Adverse Event Frequency | Completed Trial (Per Protocol) | 0.25 Number of SAEs/participant | Standard Deviation 0.46 |
Primary
Serious Adverse Event Frequency, Participant Count
Number participants with at least one documented serious adverse event, count
Time frame: Total during 24-week trial
Population: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin, Intranasal | Serious Adverse Event Frequency, Participant Count | Enrolled | 2 Participants |
| Insulin, Intranasal | Serious Adverse Event Frequency, Participant Count | Completed Trial (ITT) | 1 Participants |
| Insulin, Intranasal | Serious Adverse Event Frequency, Participant Count | Completed Trial (Per Protocol) | 0 Participants |
| Placebo, Intranasal | Serious Adverse Event Frequency, Participant Count | Enrolled | 2 Participants |
| Placebo, Intranasal | Serious Adverse Event Frequency, Participant Count | Completed Trial (ITT) | 2 Participants |
| Placebo, Intranasal | Serious Adverse Event Frequency, Participant Count | Completed Trial (Per Protocol) | 2 Participants |
Comparison: Analysis of Enrolled group.p-value: 0.669Fisher Exact
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
Time frame: Between baseline and week 24 visits
Population: 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.
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.
Time frame: Difference between baseline and week 24 visits
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin, Intranasal | Neurocognitive Performance: NPZ-8 Score, Week 24 Visit Score Minus Baseline Score | Completed Trial (ITT) | -0.09 z-score | Standard Deviation 0.39 |
| Insulin, Intranasal | Neurocognitive Performance: NPZ-8 Score, Week 24 Visit Score Minus Baseline Score | Completed Trial (Per Protocol) | -0.07 z-score | Standard Deviation 0.42 |
| Placebo, Intranasal | Neurocognitive Performance: NPZ-8 Score, Week 24 Visit Score Minus Baseline Score | Completed Trial (ITT) | -0.01 z-score | Standard Deviation 0.57 |
| Placebo, Intranasal | Neurocognitive Performance: NPZ-8 Score, Week 24 Visit Score Minus Baseline Score | Completed Trial (Per Protocol) | -0.02 z-score | Standard Deviation 0.6 |
Secondary
Neuroimaging Markers: ASL, Week 24 Visit Value Minus Baseline Value
Arterial spin labeling (ASL), a novel measure of cerebral blood flow
Time frame: Changes between baseline and week 24 visits
Population: Collected data were not considered valid due to an equipment malfunction.
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).
Time frame: Changes between baseline and week 24 visits
Population: 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
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Insulin, Intranasal | Neuroimaging Markers: Diffusion Weighted Imaging, Whole Brain Mean Diffusivity, Week 24 Visit Value Minus Baseline Value | All Available | 4.7274*10^-6 m^2/s |
| Insulin, Intranasal | Neuroimaging Markers: Diffusion Weighted Imaging, Whole Brain Mean Diffusivity, Week 24 Visit Value Minus Baseline Value | Per Protocol | 5.8845*10^-6 m^2/s |
| Placebo, Intranasal | Neuroimaging Markers: Diffusion Weighted Imaging, Whole Brain Mean Diffusivity, Week 24 Visit Value Minus Baseline Value | All Available | 4.1177*10^-6 m^2/s |
| Placebo, Intranasal | Neuroimaging Markers: Diffusion Weighted Imaging, Whole Brain Mean Diffusivity, Week 24 Visit Value Minus Baseline Value | Per Protocol | 1.1278*10^-5 m^2/s |
Comparison: Analysis for All Available group (participants who had both Baseline and Week 24 scans).p-value: 0.98t-test, 2 sided
Comparison: Analysis for Per Protocol group.p-value: 0.86t-test, 2 sided
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).
Time frame: Changes between baseline and week 24 visits
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin, Intranasal | Neuroimaging Markers: DTI, Whole Brain Mean Fractional Anisotropy (FA), Week 24 Visit Value Minus Baseline Value | All Available | -0.0011885 index | Standard Deviation 0.0055178 |
| Insulin, Intranasal | Neuroimaging Markers: DTI, Whole Brain Mean Fractional Anisotropy (FA), Week 24 Visit Value Minus Baseline Value | Per Protocol | -0.0022483 index | Standard Deviation 0.0035673 |
| Placebo, Intranasal | Neuroimaging Markers: DTI, Whole Brain Mean Fractional Anisotropy (FA), Week 24 Visit Value Minus Baseline Value | All Available | -0.0043236 index | Standard Deviation 0.0071927 |
| Placebo, Intranasal | Neuroimaging Markers: DTI, Whole Brain Mean Fractional Anisotropy (FA), Week 24 Visit Value Minus Baseline Value | Per Protocol | -0.0048070 index | Standard Deviation 0.0076274 |
Comparison: Analysis for All Available group (participants who had both Baseline and Week 24 scans).p-value: 0.366t-test, 2 sided
Comparison: Analysis for Per Protocol group.p-value: 0.505t-test, 2 sided
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).
Time frame: Changes between baseline and week 24 visits
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, Choline, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | -0.1495 mmol/L, approx. (institutional units) | Standard Deviation 0.3583 |
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, Choline, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | -0.1905 mmol/L, approx. (institutional units) | Standard Deviation 0.4548 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, Choline, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | 0.1907 mmol/L, approx. (institutional units) | Standard Deviation 0.4769 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, Choline, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | 0.1162 mmol/L, approx. (institutional units) | Standard Deviation 0.4757 |
Comparison: Comparisons of change from W0 to W24 between treatment and placebo are based on a mixed effects regression model using a two-sided Wald test of the interaction term for treatment and time.p-value: 0.244Wald test, two-sided
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).
Time frame: Changes between baseline and week 24 visits
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, Choline, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | 0.1670 mmol/L, approx. (institutional units) | Standard Deviation 0.343 |
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, Choline, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | 0.2028 mmol/L, approx. (institutional units) | Standard Deviation 0.4017 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, Choline, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | -0.1557 mmol/L, approx. (institutional units) | Standard Deviation 0.213 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, Choline, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | -0.2128 mmol/L, approx. (institutional units) | Standard Deviation 0.1795 |
Comparison: Comparisons of change from W0 to W24 between treatment and placebo are based on a mixed effects regression model using a two-sided Wald test of the interaction term for treatment and time.p-value: >0.25Wald test, two-sided
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).
Time frame: Changes between baseline and week 24 visits
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, Myoinositol, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | 0.7855 mmol/L, approx. (institutional units) | Standard Deviation 0.8485 |
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, Myoinositol, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | 0.5373 mmol/L, approx. (institutional units) | Standard Deviation 0.8859 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, Myoinositol, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | 0.4759 mmol/L, approx. (institutional units) | Standard Deviation 0.8174 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, Myoinositol, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | 0.3022 mmol/L, approx. (institutional units) | Standard Deviation 0.7404 |
Comparison: Comparisons of change from W0 to W24 between treatment and placebo are based on a mixed effects regression model using a two-sided Wald test of the interaction term for treatment and time.p-value: >0.25Wald test, two-sided
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).
Time frame: Changes between baseline and week 24 visits
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, Myoinositol, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | 0.2617 mmol/L, approx. (institutional units) | Standard Deviation 1.8493 |
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, Myoinositol, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | 0.6063 mmol/L, approx. (institutional units) | Standard Deviation 2.1711 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, Myoinositol, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | 0.2155 mmol/L, approx. (institutional units) | Standard Deviation 1.1215 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, Myoinositol, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | 0.0382 mmol/L, approx. (institutional units) | Standard Deviation 1.156 |
Comparison: Comparisons of change from W0 to W24 between treatment and placebo are based on a mixed effects regression model using a two-sided Wald test of the interaction term for treatment and time.p-value: >0.25Wald test, two-sided
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).
Time frame: Changes between baseline and week 24 visits
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | -0.5572 mmol/L, approx. (institutional units) | Standard Deviation 0.927 |
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | -0.7895 mmol/L, approx. (institutional units) | Standard Deviation 1.1018 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | -0.1870 mmol/L, approx. (institutional units) | Standard Deviation 0.8497 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Basal Ganglia, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | -0.2915 mmol/L, approx. (institutional units) | Standard Deviation 0.8801 |
Comparison: Comparisons of change from W0 to W24 between treatment and placebo are based on a mixed effects regression model using a two-sided Wald test of the interaction term for treatment and time.p-value: >0.25Wald test, two-sided
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).
Time frame: Changes between baseline and week 24 visits
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | 0.1050 mmol/L, approx. (institutional units) | Standard Deviation 1.7154 |
| Insulin, Intranasal | Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | 0.2597 mmol/L, approx. (institutional units) | Standard Deviation 2.1606 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Available MRS Secondary Outcomes | 0.1432 mmol/L, approx. (institutional units) | Standard Deviation 0.6497 |
| Placebo, Intranasal | Neuroimaging Markers: SV-MRS, N-acetyl Aspartate, Frontal White Matter, Week 24 Visit Value Minus Baseline Value | Completed Trial (Per Protocol) | 0.1134 mmol/L, approx. (institutional units) | Standard Deviation 0.7218 |
Comparison: Comparisons of change from W0 to W24 between treatment and placebo are based on a mixed effects regression model using a two-sided Wald test of the interaction term for treatment and time.p-value: >0.25Wald test, two-sided