Clinical Trial of Intranasal Insulin for the Treatment of HIV-associated Neurocognitive Disorder (HAND)
Phase: PHASE1
Conditions: HIV Dementia, HIV-Associated Cognitive Motor Complex
Sponsor: Johns Hopkins University

 
 
JHMIRB eFormA  IRB00108564  v3.1_180926 
Version 3 Dated:   06/2007 
 
 
 
 
 
 
Document Title: JHMIRB eFormA IRB00108564 v3.1_180926 
ClinicalTrials.gov ID: NCT03081117 
Document Date: 10/16/2018 
 
Description: Protocol for Intranasal Insulin for the Treatment of HAND as formatted for The Johns Hopkins University IRB 
[eForm A] including plan for statistical analysis. Version 3.1 was submitted to the Johns Hopkins IRB on 9/26/2018 and 
approved by the IRB on 10/16/2018 without changes. The protocol was current as of the last participants to consent and enroll. 
23 pages (excluding cover)

 
 
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Date 9/26/2018   
Principal Investigator:  Ned Sacktor, MD 
Application Number: IRB00108564 
 
 
 
JHM IRB - eForm A – Protocol 
 
 
 
 Use the section headings to write the JHM IRB eForm A, inserting the appropriate material 
in each. If a section is not applicable, leave heading in and insert N/A. 
 When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at 
the top of JHM IRB eForm A. 
 
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1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the research 
hypothesis, and the importance of the research. 
HIV-1-associated neurocognitive disorders (HAND) are characterized by disabling cognitive, 
behavioral, and motor dysfunction and can occur in up to 50% of HIV+ individuals even with 
combination antiretroviral therapy (ART) (1).  The mechanisms for these residual impairments are not 
fully understood, but appear to involve poor penetrance of antiretroviral drugs into the central nervous 
system (CNS) (2), that creates a 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 via 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.  Intranasal insulin and the drug delivery device will be purchased and distributed by 
the Johns Hopkins University Investigational Drug Pharmacy. The proposed trial uses several novel 
radiological and CSF surrogate markers to monitor the effects of IMT.  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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2. 
Objectives (include all primary and secondary objectives) 
The specific objectives of the trial are as follows: 
Primary Objective: To examine the clinical effects of intranasal insulin in individuals with HIV 
associated neurocognitive disorder (HAND). 
Primary Hypotheses: 
1) Intranasal insulin will be safe and well-tolerated in HIV-infected patients. 
2) Intranasal insulin will improve neuropsychological testing performance in patients 
with HAND. 
Primary outcome measures: 
1) Serious Adverse event frequency.  
2) Cognitive performance as measured by the Global Dementia Scale (GDS) 
Secondary Hypotheses: 
1) Intranasal insulin will improve functional performance in patients with HAND. 
2) Intranasal insulin levels will be detectable in the cerebrospinal fluid (CSF) as 
determined by pharmacokinetic analysis. 
3) Fasting serum insulin levels will not be affected by the administration of intranasal 
insulin. 
Secondary Objective: To examine the effect of intranasal insulin on markers associated with 
inflammation and CNS injury in individuals with HAND.  
Hypotheses: 
1) Intranasal insulin will improve neuroimaging markers associated with CNS damage and 
decrease markers associated with inflammation in HIV-infected patients. 
2) Intranasal insulin will reduce markers of cell stress and injury while increasing energy 
substrate availability in CSF. 
3) Intranasal insulin will increase levels of brain derived neurotrophic factor (BDNF) and 
amyloid-beta (Aβ) in CSF. 
Secondary outcome measures: 
1) Neuroimaging: 
i. Single voxel-magnetic resonance spectroscopy (SV-MRS) myoinositol, 
choline, and N-acetyl aspartate concentrations in frontal white matter and 
basal ganglia 
ii. Diffusion tensor imaging (DTI) whole brain fractional anisotropy, DTI whole 
brain mean diffusivity 
iii. Arterial spin labeling (ASL), a novel measure of cerebral blood flow 
2) CSF biomarkers: 
i. Ceramide, Sphingomyelin, citrate, neurofilament protein. 
ii. BDNF, protein carbonyl, Aβ-42. 
 

 
 
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3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research) 
 
SIGNIFICANCE/PUBLIC HEALTH CONTEXT OF THE STUDY 
HAND continues to be an important neurological complication of HIV infection in the era of ART.  HAND 
has a significant impact on cognitive and functional abilities (5) including employment status, driving ability, 
and medication adherence (6-11) that influence quality of life and longevity.  The future treatment for HAND 
will likely need to include both ART and an effective adjunctive therapy to treat CNS-specific pathogenetic 
mechanisms.  The urgency of this unmet need prompted us to search for an FDA approved drug that could be 
repurposed to treat HAND.  Previous studies of the pathophysiology of insulin function in the CNS, the 
pathophysiology of insulin resistance in HAND, and our preliminary finding in tissue culture and rodent 
models of HAND strongly support the use of intranasal insulin as a potential therapeutic agent to treat 
HAND. 
 
 
PRELIMINARY STUDIES FROM NON-CLINICAL AND CLINICAL STUDIES 
Insulin resistance and HAND 
Previous studies have demonstrated that insulin resistance is associated with cognitive dysfunction in patients 
with HIV infection, especially in older patients ≥ age 50 years (3, 12).  In the Hawaii Aging with HIV cohort, 
the mean serum insulin levels increased in HIV+ individuals with normal cognition (12.2), minor cognitive 
motor disorder (14.3), and dementia (17.1) [p=0.043, OR 1.036 (1.004-1.072) per unit of insulin], 
presumably as a compensatory mechanism for insulin resistance.  When HIV+ individuals greater than age 
50 years were examined, the strength of the association increased:  mean insulin levels= 10.3, 15.04, and 
19.0 for HIV+ individuals with normal cognition, minor cognitive motor disorder, and dementia, respectively 
[p= 0.003, OR 1.088 (1.030-1.149) per unit of insulin] (13).  In a more recent study of 1036 women from the 
Women’s Interagency HIV study (WIHS) cohort, higher insulin resistance as measured by the Homeostasis 
Model Assessment (HOMA) was associated with worse neurocognitive performance on the Stroop Color-
Naming test, again suggesting that insulin resistance is associated with impaired cognition in HIV+ patients 
(3). 
 
Neuroprotective effects of intranasal insulin 
Our primary choice for the selection of intranasal insulin in the clinical trial of this project is intranasal 
insulin.  Insulin is involved in the regulation of CNS functions such as food intake, metabolism, learning and 
memory, and neuronal survival. Receptors for insulin are widely distributed throughout the brain and are 
concentrated in the olfactory bulb, cerebral cortex, hypothalamus, hippocampus, cerebellum and choroid 
plexus.  Disturbances in insulin sensitivity associated with diabetes mellitus impair cognitive function, and 
improving metabolic control in individuals with diabetes improves cognitive performance (14, 15). At the 
cellular level, insulin has been shown to regulate neuronal excitability, receptor expression, trafficking and 
function. 
Exogenous administration of insulin protects neurons from a variety of insults including ischemia, oxidative 
stress, and glutamate induced excitotoxicity.  This general neuroprotective effect of insulin involves the 
induction of CREB  (cAMP response element binding protein a transcription factor that binds to CRE cAMP 
(response elements) and has an important role in learning and  memory (16) (See Figure 1). Genes regulated 
by CREB include c-fos, BDNF, tyrosine hydroxylase, and a number of neuropeptides (somatostatin, 
enkephalin, VGF, and CRF). BDNF binds TrkB and p75 on neurons and promotes survival pathways.  A 
signaling pathway that is activated by insulin and BDNF modulate learning and memory, neuroprotection 
and the regulation of food intake and glucose (17). The BDNF-activated pathway involves 
phosphatidylinositol 3-kinase and Akt kinase.  Activation of this pathway has a crucial role in learning and 
memory, is neuroprotective in models of Alzheimer’s, Parkinson’s and Huntington’s disease, and improves 
peripheral glucose metabolism by enhancing insulin sensitivity (18).  Insulin also decreases levels of 
amyloid-beta (Aβ), the toxic protein associated with Alzheimer’s disease (19), and protects against the 
deleterious effects of Aβ oligomers on synapses (20-22).  

 
 
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Figure1.  Neuroprotective effect of insulin via induction of CREB 
  
These general neuroprotective and restorative effects of insulin suggest that insulin may also be protective 
against HAND.  However, peripheral administration of insulin can be associated with hypoglycemia.  To 
circumvent this potential problem, insulin has been delivered directly to the brain using an intranasal device.  
Intranasal administration of insulin provides rapid delivery of insulin to the CNS via bulk flow along 
olfactory and trigeminal perivascular channels, and slower delivery via olfactory bulb axonal transport (19).  
Intranasal insulin also has the advantage of not adversely affecting blood insulin or glucose levels as has 
been demonstrated in previous studies in humans (19).  Intranasal insulin increases insulin levels in CSF to 
biologically relevant concentrations within 30-40 minutes and acutely enhances memory in human studies 
(23).  In a recent study conducted by our collaborator/consultant Dr. Suzanne Craft, 104 individuals with 
amnestic mild cognitive impairment or Alzheimer’s disease administered intranasal insulin showed 
improvement in neuropsychological testing, and general cognitive abilities as measured by the ADAS-cog 
score (a commonly used outcome measure in trials for Alzheimer’s disease).  Placebo-assigned patients in 
the study (19) also showed decreased fluorodeoxyglucose 18F uptake in parietotemporal, frontal, precuneus, 
and cuneus regions, whereas a matched group of insulin-treated patients showed no decline suggesting 
improvement in brain metabolism with insulin treatment.  These positive changes in memory and function 
were also associated with changes in CSF Aβ42 levels.  No significant adverse events were reported in this 
study. 
 
Anti-inflammatory effects of intranasal insulin 
Despite ART and suppression of plasma HIV replication, systemic and CNS inflammatory markers remain 
elevated in HIV infection.  Intranasal insulin may have anti-inflammatory effects, which would be of benefit 
for the treatment of HAND.   Anti-inflammatory effects have been observed with low doses of insulin in 
peripheral circulation (19, 24).  Specifically, low dose insulin infusion in diabetic patients suppressed plasma 
concentration of chemokines including monocyte chemoattractant protein-1 (MCP-1), regulated on activation 
normal T-cell expressed and secreted (RANTES) and their receptors, chemokine receptor (CCR)-2 and CCR-
5, in peripheral blood mononuclear cells (25). Insulin has also suppressed intranuclear nuclear factor Kβ 
(NFKβ), Egr-1 binding in peripheral blood mononuclear cells, and the plasma concentrations of adhesion 
molecules and cytokines, matrix metalloproteinases, tyrosine factor, plasminogen activator inhibitor-1, and 
vascular endothelial growth factor (25, 26). The effects of intranasal administration of insulin on CNS 
inflammation in HIV+ individuals have not been determined. Table 1 summarizes the outcomes reported in 
clinical studies using intranasal insulin with doses ranging from 10 to 160 IU. 
 
 
 

 
 
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Table 1. Summary of Intranasal insulin trials 
REFERENCE 
PATIENT 
POPULATION 
DOSE OF INTRANASAL 
INSULIN TESTED 
COGNITIVE ASSESSMENT  
TOOL 
Benedict, 2004 
Healthy 
160 IU (long-term) 
 
Word list (immediate recall) 
 
Word list (delayed recall) 
Reger, 2006 
Probable AD or 
MCI vs. healthy 
20 or 40 IU  (acute) 
 
Story recall (sum of immediate + delayed recall) 
 
Word list (sum of immediate + delayed recall) 
Benedict, 2007 
Healthy men 
20 IU Aspart* vs. 20 IU Regular 
(long term) 
*rapid acting 
 
Word list (immediate recall) 
 
Word list (delayed recall) 
Benedict, 2008 
Healthy, normal weight, 
with no medications 
160 IU  (acute) 
 
Digit span (immediate recall) 
 
Object location (immediate recall) 
 
Mirror tracing (immediate recall) 
Hallschmid, 2008 
Obese men 
160 IU  (long-term) 
 
Word list (delayed recall) 
 
Word list (immediate recall) 
 
Word list (delayed recall 
Reger, 2008 
AD or MCI 
20 IU  (long term) 
 
Memory saving score (immediate recall/20-min 
delayed recall ratio) 
 
Voice onset time (immediate recall/20-min delayed 
recall ratio) 
Reger, 2008 
AD or MCI vs. healthy 
10, 20, 40, 60 IU  (acute) 
 
Story recall (immediate recall) 
 
Word list learning (immediate recall) 
 
Story recall (delayed recall) 
 
Word list learning (delayed recall) 
Krug, 2010 
Healthy 
postmenopausal 
women 
160 IU (acute) 
 
Digit span (immediate recall) 
 
Object location(immediate recall) 
Fan, 2011 
schizophrenic 
I40 IU  (acute) 
 
Hopkins Verbal Learning Test (Immediate recall) 
 
Hopkins Verbal Learning Test (Delayed ) 
Craft, 2012 
AD or MCI 
20 or 40 IU 
 
Story recall (delayed recall) 
McIntyre, 2012 
Euthymic with bipolar 
disorder 
40 IU  (long term) 
 
California Verbal Learning Test, second edition 
 
Process Dissociation Task 
Novak , 2013 
Diabetic 
40 IU  (long term) 
 
Brief Visuospatial Memory Test-Revised 
 
Verbal fluency measures 
Fan, 2013 
schizophrenic 
40 IU (long term ) 
 
Positive and Negative Syndrome Scale (PANSS) 
 
Scale for Assessment of Negative Symptoms 
(SANS) 
 
Cognitive battery. 
 
Rationale for primary objective 
We will conduct a 24 week double-blinded, placebo-controlled Phase I/II trial of intranasal insulin for the 
treatment of HAND in 40 individual subjects. The Johns Hopkins HIV Neurology group has participated in 
multiple clinical trials for the treatment of HAND including studies of abacavir, selegiline (ACTG 5090), 
minocycline (ACTG 5235, N. Sacktor PI), and paroxetine/fluconazole (NA_00037283).  In the 
paroxetine/fluconazole study which required a lumbar puncture, 45 HIV+ individuals were enrolled over 48 
months. Thus, the goal of recruiting 40 HIV+ individuals within a 36 month period as proposed in the current 
study is feasible. The gold standard for identifying patients with HAND remains neurological evaluation and 
neuropsychological (NP) test performance.  Aim 1 will evaluate whether intranasal insulin for 24 weeks is 
safe and well tolerated and secondarily, improves cognitive impairment and functional performance in 
individuals with HAND.  We anticipate that surrogate markers will further support and may extend the 
neuropsychological test results. 

 
 
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4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
b. Study duration and number of study visits required of research participants. 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. 
e. Justification for inclusion of a placebo or non-treatment group. 
f. Definition of treatment failure or participant removal criteria. 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
Study Design 
The study is designed as a 24 week double-blind, placebo-controlled Phase I/II clinical trial. Participants will 
be randomly assigned to one of two groups: 1) intranasal regular insulin or 2) placebo. The investigational 
product will be administered at the daily dose of 40 IU insulin (20 IU insulin twice a day, 30-60 minutes after 
a meal, i.e., after breakfast and dinner) or equal volume, twice daily placebo. Both will be administered with 
a nasal drug delivery device [POD, Impel Neuropharma Inc., Seattle, Washington]. The device works by 
releasing a metered dose of the investigational product into a chamber covering the participant’s nose, which 
is then inhaled by breathing regularly for 2 minutes until the prescribed dose is delivered. The dose of 
intranasal insulin prescribed in this protocol is also currently being tested in a large multicenter study for the 
treatment of Alzheimer’s disease because of its safety and efficacy as a neuroprotective strategy in prior 
trials for Alzheimer’s disease.[Suzanne Craft – personal communication] The investigational product will be 
purchased by the JHU Investigational Drug Pharmacy, which will also perform randomization. A computer 
generated block randomization plan will ensure an approximately equal distribution of subjects (20 in each 
group) among the two treatment groups. 
Prior to the baseline study visit, the protocol requires two visits during which screening assessments and 
procedures are performed. Randomization, start of study drug, and enrollment in the trial occur at the 
baseline visit. Once enrolled there are monthly follow-up visits focused on safety labs, monitoring adverse 
events, and assessing compliance with study drug administration. Outcome measures are collected at the 
baseline, week 12, and week 24 visits (details provided below). Those participants who agree to the optional 
pharmacokinetics portion of the protocol will have additional procedures at a week 1 and week 4 visit as well 
as the week 12 visit (see details for optional PK portion of the protocol below). 
Use of placebo and blinding in this protocol is justified by the higher scientific validity of the double-blind, 
placebo-controlled trial design, given that there is currently no FDA approved alternative treatment for 
HAND and there is no evidence that the target population of this study is being denied care or at increased 
risk of harm if given placebo instead of the investigational product. Blinding will not put any undue burden 
on the participant or study team. The investigational product and placebo will look identical for all 
participants, and the integrity of blinding will be assessed by participant and researcher questionnaires. A 
Data Safety Monitoring Board (DSMB) will regularly review unblinded safety data. Participation in this 
study will not require a change in either routine care or current therapy. 
Human Subject Selection 
The study involves the recruitment of 40 individuals with HIV infection and cognitive impairment over three 
to four years. Study participants will include only adults (18 to 69 years old) and will be non-institutional 
(i.e., no prisoners). Study candidates who are too cognitively impaired to provide informed consent will not 
be enrolled because they are unlikely to be able to complete the protocol specified neurocognitive 
evaluations. Individuals over the age of 69 are also excluded from this study to avoid potential confounding 
effects of age-related decline in cognitive functioning. 
Individuals with significant difficulty speaking, reading or writing English, or who have completed less than 
7th grade education level will be excluded because they may provide inaccurate neuropsychological testing 
results or have difficulty completing the neuropsychological testing procedures. We currently do not have 
comparable neuropsychological measures and normative data for languages other than English. 

 
 
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Women who are pregnant or nursing will not be enrolled in the study due to, 1) the Category B status of 
insulin, and 2) the procedures and data collection needed to assess risk to fetus or nursing baby are outside 
the scope of this protocol. Participants who are able to become pregnant will be required to use appropriate 
methods of contraception for the trial duration, and all women able to become pregnant will be evaluated 
with a pregnancy test at screening and follow-up visits. Women 55 years of age and over who have not had a 
period for one year will be considered menopausal and will not need pregnancy testing or contraception. 
Women under age 55 will undergo pregnancy testing and will be required to use appropriate methods of 
contraception for the trial duration, unless there is a history of hysterectomy, bilateral oophorectomy, or 
medically-documented ovarian failure. Adequate methods of contraception include:  implanted 
contraception, intrauterine device in place for at least 3 months, or barrier method in conjunction with 
spermicide. Women of childbearing potential must have a negative pregnancy test at screening and be non-
lactating. 
In the event of pregnancy, the study agent will be discontinued but the subject will remain on study through 
pregnancy outcome for safety monitoring; a report of the pregnancy will be made to the DSMB and IRB; and 
the participant will be advised to notify their obstetrician of exposure to the study agent. 
It is justified to exclude children because of the low incidence of HIV infection among children, and because 
it would not be feasible to use these clinical tests (serial lumbar punctures) on children. In addition, age-
appropriate neuropsychological tests would be needed and normative data for some of the 
neuropsychological tests are not available in children. Finally, imaging children would require sedation.  For 
these reasons, we will NOT be studying children. The proposed cohort will be representative of the epidemic 
in Maryland. We estimate that we may need to screen up to 100 candidates in order to enroll 40 participants. 
Clinical assessments 
The screening visit and clinical assessments will include standard demographic information, medical history, 
antiretroviral medication history, alcohol and illicit substance use, and other medical illnesses. The 
neurological examination will include the ACTG macro-neurological examination (54). The schedule of 
events is detailed in Table 2. 
Table 2 
Evaluating 
Screen 
Pre-
entry 
Baseline 
Wk. 
1 
Wk. 
4 
Wk. 
8 
Wk. 
12 
Wk
16 
Wk 
20 
Wk. 
24 
HIV documentation; 
Incl./exclusion assessment 
X 
X 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
   X(‡) 
X(‡) 
X(‡) 
X 
 X(‡) 
X 
X 
X 
Concomitant medications 
X 
 
   X(‡) 
X(‡) 
X(‡) 
X 
 X(‡) 
X 
X 
X 
Neurological exam 
X 
 
X 
 
 
 
X 
 
 
X 
Neuropsychological tests 
X 
X 
X 
 
 
 
X 
 
 
X 
Beck depression inventory 
X 
 
X 
 
 
 
X 
 
 
X 
HAND Rating Scale 
X 
 
X 
 
 
 
X 
 
 
X 
Functional, quality of life, 
fatigue assessments 
X 
 
X 
 
 
 
X 
 
 
X 
Blood draw 
X 
X 
   X(‡) 
(‡) 
 X(‡) 
X 
 X(‡) 
X 
X 
X 
Urine tests 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy test 
X 
 
X 
 
X 
 
X 
 
 
X 
Optional Lumbar 
puncture/CSF tests  
 
(X)(‡) 
 
 
 
 
(‡) 
 
 
(X) 
MRI scan 
 
 
X 
 
 
 
 
 
 
X 
Study drug compliance 
assessment 
 
 
 
X(‡) 
X(‡) 
X 
X(‡) 
X 
X 
X 
Smell function test 
 
 
X 
 
 
 
 
 
 
X 
Blinding Questionnaire 
Investigator/Subject 
 
 
 
 
 
 
 
 
 
X 
(‡)Optional pharmacokinetics study – additional procedures/biosamples/assessments 
 

 
 
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Neuropsychological (NP) testing is repeated on three occasions during the screening-baseline period to 
reduce changes due to practice effects during the 24 week period. During the trial, NP testing will be 
repeated at weeks 12 and 24. The NP test battery (Table 3) consists of 13 tests that cover 7 major cognitive 
domains, and it takes 60-75 minutes to complete. The tests have been shown to be sensitive to the earliest 
cognitive changes associated with HAND.(9) Z-scores will be calculated for each neuropsychological test 
using age and education adjusted norms to define cognitive impairment (see Section 5, inclusion criterion 
number 4). An optional baseline lumbar puncture (LP) will be performed during pre-entry on participants 
who are able and willing to undergo the procedure. 
Week 4 evaluations include vital signs, blood tests, and, as needed, a targeted physical examination if the 
participant reports an AE requiring follow up. At weeks 12 and 24 evaluations will include the clinical 
assessments, neurological examination, safety evaluations/blood tests, NP testing, depression assessment, 
functional assessments and optional lumbar puncture (week 24/final visit). The optional pharmacokinetics 
procedures (see below) will include additional blood draws (baseline, week 1, week 4, week 12) and LP 
(week 12). A smell function test will be performed at baseline and week 24 visits to assess risk of changes to 
olfactory sensation. If a participant raises subjective symptoms suggesting altered or impaired smell during 
the trial, the study team will perform additional smell tests, as needed. 
 
Routine safety blood tests will include fasting glucose and insulin levels (insulin resistance measured by 
HOMA), HIV viral load, CD4/T-cell count, electrolyte panels including liver function tests, and complete 
blood counts performed at screening, pre-entry, baseline, monthly after baseline, and, if deemed necessary by 
the investigator, ad hoc visits for safety evaluation. In addition there are non-routine blood tests performed 
prior to enrollment (refer to Table 1 in Appendix A, page 23, for complete schedule of lab tests). Urine 
toxicology screens will be performed at screening, pre-entry, baseline, and weeks 4, 8, 12, 18, 20 and 24. 
Routine safety labs will be performed in real time by the Johns Hopkins Hospital Laboratory Services 
(JHHLS). CSF specimens will be collected at the pre-entry visit and week 24 visit. CSF differential cell 
count, as well as protein and glucose levels will be performed by the JHHLS, while CSF samples for HIV 
RNA levels, fasting insulin levels, and outcome measures will be stored in a -80 degree C freezer for assays 
to be run at the conclusion of the study. 
Table 3. Neuropsychological Test Battery 
Cognitive Domain 
Test/Subtests 
Time 
(Mins) 
Verbal memory 
Hopkins Verbal Learning Test 
   Delayed recall score 
   Delayed recognition score 
20 
 
 
Visual Memory 
Rey Complex Figure  
   Delayed recall score 
3 
Visuo-construction 
Rey Complex Figure 
   Copy score 
20 
Psychomotor 
Symbol Digit Modalities Test   
Trail Making Test A  
Computerized Reaction Time 
Test (CalCAP) 
   Simple reaction time score 
   Choice reaction time score  
3 
2 
10 
Motor Speed (fine) 
Grooved Pegboard 
   Dominant hand score 
   Non-dominant hand score 
5 
Motor Speed (gross) 
Timed Gait 
2 
Frontal/Executive 
Trail Making Test B  
Verbal Fluency (F,A,S) Test 
Stroop Color Interference 
3 
5 
5 
Screening tests 
International HIV Dementia 
Scale 
3 
Literacy (baseline only) 
National Adult Reading Test 
5 
 

 
 
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Unblinded data, including adverse events and toxicities, will be made available to a DSMB who will review 
semiannual closed reports (from PI) and open reports (from site pharmacist, the only unblinded member of 
the study team). 
 
Participants will be removed: 1) if they develop a side effect, laboratory abnormality or medical condition 
that, in the opinion of the investigator, constitutes a significant safety risk for the subject; or 2) if a study 
participant is noncompliant with study medications as prescribed or unable to comply with study 
assessments. A study participant can stop participation in the study at any time or choose premature 
discontinuation of the investigational product (with continued follow up visits for intent to treat analysis). At 
the conclusion of the study, a participant’s therapy will end and the participant will receive routine clinical 
care, including Department of Neurology consultation services if requested. 
 
Therapy and Follow-up When the Study Ends or Participation Ends Prematurely 
When the study ends, we will give participants the option of setting up a clinical appointment with the PI to 
assess options for follow up care. 
In order to help evaluate safety, participants who stop their study drugs prematurely may be asked to return 
for their regularly scheduled visits. If a participant discontinues the investigational product due to an AE 
possibly or definitely attributed to the study drug, the study team will ask the participant to return for all 
remaining visits and procedures for intent-to-treat analyses. Follow-up for all other study drug 
discontinuations, either directed or undirected, will be evaluated based on: 1) reason for discontinuation, 2) 
the number of days following baseline when the study drug was stopped, and 3) the estimated total 
(cumulative) dose of study drug up to the point of discontinuation. 
If the participant must altogether leave the study prematurely, we will ask the participant to come in for a 
final visit. At this final visit we will ask the participant to return all unused doses of the study drug, as well as 
the POD, and ask him/her to complete questionnaires, including the blinding questionnaire. The PI may also 
request certain tests or procedures from the study visits not yet completed. Returning to perform incomplete 
tests or procedures at the final visit will be requested at the PI’s discretion after reviewing the reason for 
leaving the study and assessing how much of the study has been completed up until the time of leaving. 
 
Neuroimaging protocol 
The MRI study will be performed on the commercial Philips Trio 3.0 Tesla scanner, using the Philips phase-
array head coil and the following protocols: 
Standard MRI protocol: The MRI protocol includes a 3-plane localizer (TR/TE = 20/5 ms; 1 NEX; 
128x256x1), a sagittal 3D MP-RAGE (TR/TE/TI = 2200/4.91/1000 ms; 1 NEX; 256x256x160), and an axial 
FLAIR sequence (TR/TE = 10,000/85 ms; 1 NEX; 205x320x28) to rule out any focal brain abnormalities. 
MRI scans will be reviewed by a site radiologist within one week for possible lesions (neoplasm, stroke, 
opportunistic infections); if clinically significant lesions are found (or incidental findings), we will 
immediately inform the participant and if serious his/her physician. 
Quantitative 1H MRS protocol: Single-voxel 1H spectra will be acquired using a customized protocol [which 
includes water T2 measurement] that is based on the product version of the PRESS sequence. Voxels 6 cc in 
volume will be prescribed in 4 regions: midline frontal gray matter, right mid-frontal centrum semiovale 
(white matter), right basal ganglia (deep gray matter), and parietal cortex gray matter. Field homogeneity and 
water suppression will be adjusted using automated algorithms. Water suppressed spectra will be collected 
with TE/TR = 30/3000ms, bandwidth = 2000 Hz, 128 averages, 8-step phase cycling. The short TE yields 
excellent signal-to-noise ratio and allows observation of coupled spin systems, such as myoinositol (mI) and 
glutamate (Glu) plus glutamine (Gln). In addition, the customized protocol will automatically collect 7 
single-scan, fully relaxed water FIDs from each voxel at variable echo times (TE=30, 45, 65,100, 200, 500 
and 1500 ms; TR=10 ms) from which metabolite concentrations are calculated. 
The total examination time per voxel is about 7 minutes. For quality control, a phantom spectrum will be 
obtained within 24 hours of each in vivo scan, using the identical MRS protocol as described above. 

 
 
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DTI protocol: A DTI series with whole-brain coverage will be acquired (spin-echo EPI, TR/TE = 3700/88 
ms, b=[0,1000] s/mm2, 12 directions, 4mm slices with 0.5mm gap). Apparent diffusion coefficient (ADC) 
and fractional anisotropy (FA) maps will be calculated and regions of interest (ROIs) will be manually drawn 
in a standardized fashion to assess mean diffusivity (MD) and FA, using DTI-Studio. The following regions 
will be evaluated in both right and left hemispheres: caudate, globus pallidus, thalamus, genu of corpus 
callosum, frontal white matter, and parietal white matter. Analysis of each individual ROI MD and FA as 
well as analysis of whole brain MD and FA will be performed. 
ASL protocol: ASL will be performed using the ‘FAIR’ technique with a gradient-echo EPI readout, with a 
single axial slice at the level of the head of the caudate nucleus. Our collaborators have developed 
considerable experience in using ASL to measure cerebral blood flow (CBF) and now routinely acquire ASL 
images in the human brain at 3T. We performed a study of 12 cognitively normal HIV- subjects who were 
scanned four times (at 0, 3, 6, and 12 months) and no significant difference in CBF in the medial frontal 
gyrus was found over this period 55. Data obtained from the first two scans were analyzed by two readers, 
and showed high reliability [intraclass correlation coefficient (ICC) > 0.97] and reproducibility [within 
subject coefficient of variation (wsCV) 
< 6%]. 
 
Measurement of markers of oxidative/nitrosative stress, energy metabolism, and neuronal/axonal 
injury 
Measurement of lipid markers of oxidative stress in CSF and plasma will be conducted as described 
previously (46).  The measurement of these lipid markers of oxidative stress  (e.g., ceramide, 
sphingomyelin), and energy metabolism (e.g., citrate, acetate) will be performed in the laboratory of Dr. 
Norman Haughey. CSF concentrations of protein carbonyls will be measured by Western blot as described 
previously (45) and neurofilament protein (NFL) will be analyzed using an enzyme-linked immunoassay 
(ELISA) described previously, (49), in the laboratory of Dr. Avindra Nath at NINDS.  BDNF will be 
measured by protein macroarray as described previously (51) in the laboratory of Dr. Norman Haughey. 
Insulin binding proteins 1-7 and Aβ42 will be measured using the multiplex XMAP Luminex platform 
(Luminex Corp, Austin, TX) in the laboratory of Dr. Carlos Pardo. Fasting AM CSF will be collected at the 
same time each day to prevent diurnal variation in Aβ levels.  CSF will be collected using polypropylene 
tubes to prevent Aβ from sticking to polycarbonate tubes of standard LP kits. Blood and CSF will also be 
collected and stored for additional biomarkers to be determined at the conclusion of the study. 
 
Sources of Data 
Research data and materials include blood, urine, cerebrospinal fluid (CSF), neurological exam notes, 
neuropsychological test results, functional evaluations, interview data about medical history and drug use, 
and both imaging and quantification data from cranial MRI. Most outcome data for this study are not from 
clinically validated tests or procedures and therefore will be obtained for research purposes only. However, 
routine lab tests performed by the JHH core lab, clinical exam notes by the study team physicians, and 
clinically interpreted structural MRI reports will be part of the participant’s electronic patient record and 
available for clinical use. All data obtained within this project will occur following written consent by each 
participant and will comply with HIPAA guidelines for data collection and disclosures. The confidentiality of 
the data is maintained through the use of a secure, double-lock office storage space and an encrypted, 
password-protected computer database. 

 
 
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Pharmacokinetics (PK) protocol (optional)  
An optional PK protocol will be discussed with each participant during the consent process for the clinical 
trial. Target participation for the PK protocol is 10 subjects with complete evaluable data. During the 
screening period, the study team will ask each participant if he or she would be interested in the optional PK 
procedures. The study team will also assess whether the participant could practically, reliably, and safely 
complete the extra PK procedures (e.g., is phlebotomy or LP difficult for the participant?). For each 
participant who enrolls in the clinical trial and consents to consideration for the PK testing, selection will be 
made by order of enrollment until the target of 10 subjects is reached. Participants must be able and willing 
to undergo the optional baseline LP and must decide to participate in the PK protocol during pre-entry by the 
time of LP because it requires additional CSF to be collected at that time. Participants in the optional PK 
protocol can change their minds at any time.  
The PK protocol has two components. The first will compare pre-intervention ARV levels in plasma and 
CSF with levels on intervention at Week 1 (plasma), Week 4 (plasma), and Week 12 (plasma and CSF). 
Blood and CSF will be collected in the morning before each participant takes his or her prescribed ARVs in 
order to measure pre-dose ARV Cmin concentrations. Pre-dose blood samples will also be collected at Week 1 
and Week 4. If the participant takes an ARV that can only be administered in the evening, the morning blood 
draw will be scheduled at the same time interval relative to dosing at each visit. 
The second component of the PK protocol will occur during the regularly scheduled Week 12 visit, which 
will be extended to permit 8 blood draws by peripheral intravenous access line and an LP. The timing of the 
sample collection will follow the schema in Table 4. The morning dose of insulin will be administered in the 
clinic in a supervised manner, and sampling times calculated from the observed dosing. Blood samples for 
plasma insulin and ART concentrations will be obtained as indicated. The geometric mean of concentrations 
at the PK visits will indicate the plasma 
minimum concentration of insulin. 
Once the PK protocol accrual target is 
met, the stored specimens will be 
transferred to the research laboratories 
responsible for testing. Insulin levels will 
be measured by ELISA (this is more 
sensitive than mass spectrometry) in the 
laboratory of Dr. Barbara Slusher. ART 
drug concentrations will be assayed in the 
Clinical Pharmacology Analytical 
Laboratory by Dr. Mark Marzinke using 
methods as described previously (68, 69). 
Common antiretroviral drugs including 
tenofovir, emtricitabine, efavirenz and 
several newer drugs including maraviroc 
and dapivirine will be measured. 
Upon transfer of the specimens, the research pharmacist will provide Drs. Slusher and Marzinke with the 
treatment allocations associated with each set of specimens. A separate PK protocol specimen ID, (different 
from the clinical trial subject ID) will be used to identify each of the specimens. The treatment blinding will 
be lifted for those 10 subject specimens only and limited to Drs. Slusher and Marzinke. Communication 
between the research labs and the rest of the study team will be limited to only that which is necessary to 
transfer and carry out the procedures in order to avoid possible compromise to the treatment blinding. The 
research labs will not be able to link the PK protocol specimen IDs to the clinical trial subject IDs, clinical 
PHI, or other personal identifiers. 
 
 
Table 4.  Pharmacokinetic Study Schedule (Week 12 Visit) 
Time following dose 
administration 
(minutes) 
Blood 
draw 
CSF 
collection 
Neuropsychological 
testing 
0 
X 
 
 
10 
X 
 
 
30 
 
X 
 
45 
X 
 
X 
90 
X 
 
120 
X 
 
 
180 
X 
 
 
360 
X 
 
 
480 
X 
 
 

 
 
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5. 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria: 
1) HIV+ based on ELISA and confirmed by either Western blot or plasma HIV RNA, 
2) Capable of providing informed consent, 
3) Between the ages of 18-69 years, 
4) Presence of neuropsychological testing impairment as defined by performance at least 1.0 standard 
deviation below age-matched and education-matched controls on three or more independent 
neuropsychological tests at the screening visit, or performance at least 2.0 standard deviations below age-
matched and education-matched controls on one independent neuropsychological test and at least 1.0 
standard deviation below age-matched and education-matched controls on a second independent 
neuropsychological test at the screening visit, 
5) Stable HAART regimen for at least 6 months (180 days) prior to study entry, with no plans to change 
the antiretroviral regimen over the study period (confirmed by discussion with a patient’s primary 
provider), 
6) The following lab values within 2 weeks prior to entry: hemoglobin > 8.9 g/dl, absolute neutrophil 
count > 500 cells/mm3, platelet count > 50,000 cells/mm3, ALT < 2.5 X upper limit of normal, alkaline 
phosphatase < 3 X upper limit of normal, serum creatinine ≤ 2 X upper limit of normal, 
7) Negative serum or urine β-HCG pregnancy test for all women of reproductive potential (have not 
reached menopause or undergone hysterectomy, oophorectomy, or tubal ligation), 
8) Neurological examination by a physician to assess for space-occupying brain mass lesion, and if 
suspected, neuroimaging with CT or MRI must confirm the absence of a mass lesion prior to optional 
lumbar puncture and study entry, 
9) Examination by physician revealing no contraindication or current impediment to using the intranasal 
device prior to starting the trial (e.g., traumatic obstruction to nasal passage, chronic sinus infections, 
significant and symptomatic seasonal allergies, etc.), 
10) At least one plasma HIV RNA test within 12 months prior to the screening visit with results less than 
400 copies/mL, as well as plasma HIV RNA tests at both the screening visit and a pre-entry visit (within 
14 days prior to baseline/randomization) less than 400 copies/mL, 
11) No clinical signs or evidence of intoxication during screening and pre-entry visits; evidence includes 
but is not limited to urine drug toxicology testing by the study team during each visit. Prior to enrollment 
participants must produce at least three different urine drug toxicology screen test results, per protocol, in 
which cocaine, methamphetamine, and heroin (or equivalent opiate/opioid metabolite) are negative; 
marijuana (THC) must be negative in the absence of taking prescribed medications known to produce a 
positive result for marijuana (THC), such as efavirenz or cannabinoid treatments, in which case clinical 
assessment of possible marijuana intoxication will be made at the discretion of the investigator; any test 
results positive for psychoactive prescription drugs included in the toxicology screen must be explained 
by documented prescription history, and clinical assessment of possible intoxication will be made at the 
discretion of the investigator. 

 
 
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Exclusion Criteria: 
1) Current or past opportunistic CNS infection at study entry, 
2) History or current clinical evidence of schizophrenia, 
3) History of chronic neurological disorder such as multiple sclerosis or uncontrolled epilepsy, 
4) Active symptomatic AIDS defining opportunistic infection within 30 days prior to study entry, 
5) History of an uncontrolled medical illness or current severe affective disorder (e.g., depression with 
suicidal intention) which in the opinion of the investigators would constitute a safety risk for patients or 
interfere with the ability of a patient to complete the study, 
6) Exclusion from the optional lumbar puncture procedure (but not the clinical trial) if the participant is 
currently treated with anticoagulants including coumadin, heparin, or low molecular weight heparin, or if 
upon screening exam, the investigator identifies any contraindications or undue risks to undergoing 
voluntary lumbar puncture, 
7) History of diabetes or treatment with insulin or an oral hypoglycemic agent, 
8) Amylase/lipase elevation (≥ 2X upper limit of normal) within 14 days prior to baseline/randomization, 
9) Detectable plasma HIV RNA test ≥400 copies/mL within 6 months prior to baseline/randomization, 
10) History of any endocrine related cancer including any thyroid tumor, 
11) 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, 
12) HIV+ individuals with moderate or severe confounding illnesses. Specifically, the impact of 
comorbid conditions on neurocognitive performance will be examined using a comorbid condition scale 
developed by Dr. Robert Heaton at UCSD (9). The effects of comorbid conditions are rated as minimal, 
moderate, or severe in this scale. Examples of comorbid conditions included in the scale include mild 
learning disability, past substance use disorder, traumatic brain injury with loss of consciousness >30 
minutes. 
 

 
 
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6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
 
Evidence shows that the dose of 40 IU intranasal insulin (20 IU of insulin twice a day) is safe and well-
tolerated. This dose of intranasal insulin is currently being tested in a large multicenter study for the 
treatment of Alzheimer’s disease because of its safety and efficacy as a neuroprotective strategy in prior 
trials for Alzheimer’s disease.[Suzanne Craft – personal correspondence] This dose was also found to be 
efficacious in improving memory performance (water maze task) in the EcoHIV animal model for HAND. 
The intranasal drug delivery device we have chosen for the protocol [POD®, Impel NeuroPharma, Inc., 
Seattle, WA] is currently being used with regular insulin in other FDA approved clinical trials. For further 
clarification of the rationale and justification of this treatment and dose, see Section 3 of the eFormA (Table 
1 lists the literature referenced for justification of drug and dose selection).  

 
 
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7. 
Study Statistics 
a. Primary outcome variable. 
b. Secondary outcome variables. 
c. Statistical plan including sample size justification and interim data analysis. 
d. Early stopping rules. 
 
Safety and tolerability outcome measures/endpoints 
To assess the safety and tolerability of intranasal insulin, we will maintain a record of adverse events using 
standardized ACTG clinical reporting forms and provide attribution to each of these events (e.g., study drug 
related). We will compute proportions of individuals reporting these adverse events in each group. 
Safety and tolerability outcome analysis: Frequency of symptoms, signs, and toxicities by treatment will be 
examined with the Fisher’s exact test. Time from treatment initiation to the development of a toxicity and/or 
symptom or sign will be compared across treatment arms using the log rank test.  In addition, analyses will 
be performed for changes in laboratory test results, smell test results, vital signs and HIV markers for both 
this aim (e.g., HIV RNA levels) and aim 3 (e.g., surrogate measures). Variables that seriously violate the 
assumption of normality will be transformed using the natural logarithm for purposes of statistical analyses. 
Neuropsychological testing and functional performance outcome measures/endpoints 
This study also seeks to provide estimates for the effect of the two treatment groups (intranasal insulin and 
placebo) on cognitive impairment in individuals with HAND.  Each individual will be characterized on the 
basis of the arithmetic difference between week 24 and baseline NP test battery performance. The primary 
outcome measure for NP performance will be the GDS (55).  Secondary outcome measures will include the 
NPZ8, and subjective and performance based measures of functional performance. 
The GDS score weighs the number and severity of deficits in an individual’s neuropsychological test (NP) 
performance giving relatively less weight to performances within and above normal limits.  The GDS is 
computed by converting demographically corrected standard scores (T scores) on individual NP measures 
(see Table 5) to deficit scores ranging from 0 (no impairment) to 5 (severe impairment). The deficit scores 
are then averaged to create the GDS measure (55)(56). The NPZ-8 is a global measure of cognitive 
functioning from tests outlined in the neuropsychological test battery for this study and closely correlates 
with HIV dementia stage (57, 58).  The NPZ-8 is derived by taking the average of the age and education-
adjusted Z scores for five tests (see Table 5) (59-66). 
Other secondary endpoints of neuropsychological test performance will include the 24 week change in the 
individual neuropsychological tests, and the cognitive domain scores.  Each cognitive domain will be derived 
as the average standardized Z score of the neuropsychological tests that corresponds to it.  The cognitive 
domains that will be examined (and the neuropsychological tests involved) are: gross motor function (timed 
gait), fine motor function (average of Grooved Pegboard test for the dominant and non-dominant hands), 
psychomotor speed (Trail Making tests part A, Symbol Digit Modalities test, and the CalCAP choice and 
sequential reaction times), verbal memory (Hopkins Verbal Learning test-Revised, learning and delayed 
recall), visual memory (Rey complex figure delayed recall), visuo construction (Rey complex figure copy), 
and frontal/executive function (Stroop Color Interference Test, interference task, verbal fluency test, and 
Trail Making part B) (see Table 3). Depression symptomatology may be present in some patients, so the 
impact of depression symptomatology will be evaluated with the Beck Depression Inventory (67).   

 
 
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   Table 5 
Individual NP Testing Measures 
Eligibility 
Assessment 
 NPZ-8 
GDS 
Hopkins Verbal Learning Test 
 
  
Trial 3 
  
  
 
  
Trials 1-3 total 
  
  
X 
  
Delayed recall 
X 
  
X 
  
Delayed recognition 
X 
  
 
Rey Complex Figure 
 
  
Copy score 
X 
  
X 
  
Delayed recall score 
X 
  
X 
Symbol Digit Modalities Test   
 
  
Total score (120 sec) 
X 
X 
X 
Trail Making Test 
 
  
Part A, time to complete 
X 
X 
X 
  
Part B, time to complete 
X 
X 
X 
Computerized (CalCAP) Reaction Time Test 
 
  
Simple reaction time, mean 
X 
X 
X 
  
Choice reaction time, mean 
X 
X 
X 
Grooved Pegboard 
 
  
Dominant hand, time 
X 
X 
X 
  
Non-dominant hand, time 
X 
X 
X 
Timed Gait 
 
  
Three trial mean, time 
  
X 
X 
Verbal Fluency (F,A,S) Test 
 
  
Total score 
X 
  
X 
Stroop Test (Kanalli Version) 
 
  
Trial 1, colors 
  
  
 
  
Trial 2, words 
  
  
 
  
Trial 3, color interference 
X 
  
X 
Functional assessments will also be utilized to evaluate efficacy. These will include both subjective self-
evaluation of performance and potentially more objective performance-based measures of function.  
Subjective measures will include 24 week change in the Karnofsky functional performance score and the 
Instrumental Activities of Daily Living (IADL) Questionnaire.  Performance based measures of functional 
status will include the modified version of the medication management test which evaluates an individual’s 
ability to manage medications (11) in a brief 5-10 minute assessment.  Another performance based measure 
of driving capabilities, the Computerized Assessment of Mild Cognitive Impairment (CAMCI) Driving 
Simulation test will also be performed to evaluate the utility of this new functional outcome measure. 
Additional assessments of efficacy will include Quality of Life assessments.  
Neuropsychological testing and functional performance outcome analysis: We have designed the study with 
the sample size of 20 per group for a total of 40 participants. We anticipate approximately 10% loss to 
follow-up with the longitudinal data. This would result in 36 evaluable participants (18 per group). Based on 
a previous study of GDS performance in patients with HAND, our study with 18 participants per aim will 
have 80% power with an alpha= 0.05 to detect a 0.45 SD improvement in GDS. We do NOT expect that the 
current study will provide conclusive evidence of efficacy. Rather, the current study will provide estimates of 
location (mean) and spread (standard deviation) of the distribution of change in NP test performance for each 
of the two treatment groups for future studies. Through randomization, it is expected that baseline 
demographic and clinical characteristics will be equalized between the two treatment arms (intranasal insulin 
and placebo). However, in the event that there are significant baseline differences between the two treatment 
arms with respect to demographic or clinical characteristics, our statistical plan can be expanded to 
incorporate the use of linear regression to model GDS as a function of treatment arm and controlling for 
significant covariates. 
 

 
 
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Blood and CSF biomarker outcome measures/endpoints 
CSF biomarker measures include levels of ceramide, sphingomyelin, citrate, acetate, neurofilament protein, 
brain derived neurotrophic factor (BDNF), protein carbonyl, insulin binding proteins 1-7, and amyloid-beta 
(Aβ). 
Blood and CSF biomarker outcome analysis: The change in the CSF surrogate markers will be examined for 
differences between the treatment arms using the Student’s t-test in order to test for differences across the 
outcome measures. Using CSF protein carbonyl levels as an example of one of the markers which will be 
examined in this aim, in our previous data, the mean (SD) protein carbonyl level was 630.5 (141.0) among 
HIV+ individuals with normal cognition, and 859.0 (188.0) among HIV+ individuals with mild HIV 
dementia. If it is assumed that there would be no change in the protein carbonyl level from baseline to the 6 
month follow-up visit among the HIV+ individuals with HAND in the placebo arm, and the change in 
protein carbonyl level among the HIV+ individuals with HAND in a intranasal insulin arm would be on the 
order of the difference observed between the HIV+ individuals with normal cognition and HIV+ individuals 
with HAND above, then using a Student t-test on the calculated change, if we were to enroll a total of 40 
individuals and assume a 10% drop-out rate for 36 evaluable patients), we would have sufficient power 
(82%) to detect a true difference in change in protein carbonyl expression of 1.2 SD between the treatment 
arms. Based on the sample size, the proposed study will provide important preliminary data for a future 
larger study of efficacy using this marker. 
Imaging outcome measures/endpoints 
For the quantitative 1H MRS protocol, single voxels, 6 cc in volume, will be prescribed in 4 regions: midline 
frontal gray matter, right mid-frontal centrum semiovale (white matter), right basal ganglia (deep gray 
matter), and parietal cortex gray matter. Field homogeneity and water suppression will be adjusted using 
automated algorithms. Water suppressed spectra will be collected with TE/TR = 30/3000ms, bandwidth = 
2000 Hz, 128 averages, 8-step phase cycling. The short TE yields excellent signal-to-noise ratio and allows 
observation of coupled spin systems, such as myoinositol (mI) and glutamate (Glu) plus glutamine (Gln). In 
addition, the customized protocol will automatically collect 7 single-scan, fully relaxed water FIDs from 
each voxel at variable echo times (TE=30, 45, 65,100, 200, 500 and 1500 ms; TR=10 ms) from which 
metabolite concentrations are calculated. 
For the DTI protocol, apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps will be 
calculated and regions of interest (ROIs) will be manually drawn in a standardized fashion to assess mean 
diffusivity (MD) and FA, using DTI-Studio. The following regions will be evaluated in both right and left 
hemispheres: caudate, globus pallidus, thalamus, genu of corpus callosum, frontal white matter, and parietal 
white matter. Analysis of each individual ROI MD and FA as well as analysis of whole brain MD and FA 
will be performed. 
The ASL protocol will be performed using the ‘FAIR’ technique with a gradient-echo EPI readout, with a 
single axial slice at the level of the head of the caudate nucleus. 
Imaging outcome analysis: Changes in imaging measures will be based on a pre and post treatment design. 
Specifically, changes in MRS, DTI, and ASL measures from baseline to 24 weeks will be assessed through a 
Hotelling t-squared test to determine if there is an overall difference between the two treatment arms 
(intranasal insulin and placebo), using a Type 1 error level of 0.05. The Hotelling t-squared is a multivariable 
analog to the Student t-test to allow comparison of two groups on the vector of measures. 
Based on MRS changes in another study evaluating insulin infusion in HIV- individuals in which those with 
high insulin sensitivity had an increase in NAA/Cr and a decrease in Cho/Cr compared to baseline, it is 
assumed that HIV+ individuals would behave similarly to those participants with high insulin sensitivity. 
The current study will enroll 40 participants (randomly assigned to intranasal insulin or placebo). We 
anticipate approximately 10% loss to follow-up, resulting in 36 participants (18 per group). We hypothesize 
to see a similar change in brain metabolites in the intranasal insulin group. We will examine this data using a 
Student t-test of change in measures between baseline and 24 weeks. The current design has adequate power 
to detect an increase in NAA/Cr (power=0.91) and a decrease in Cho/Cr (power =0.86) among HIV+ 
individuals in the intranasal insulin group relative to the placebo group. Power calculations were made using 
sampsi (Stata version 12, Stata Corp. College Station TX). 
It is anticipated that randomization will ameliorate any baseline demographic and clinical characteristics 
between the two treatment arms. If this is not the case, our statistical plan can be expanded to incorporate the 

 
 
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use of linear regression to model brain metabolites as a function of treatment arm and controlling for 
significant covariates. MRS, DTI, and ASL markers, will be compared using both a nonparametric (Mann-
Whitney U-test) and parametric (Students t-test) significance test. Bonferroni correction and also a false 
discovery rate (FDR) correction will be applied to control for multiple comparisons. Two-tailed tests will be 
used. Differences will be judged significant at p < 0.05 without correction, and at p< 0.05/N with Bonferroni 
correction, where N is the number of regions compared. Our pilot study evaluating these neuroimaging 
markers after treatment with intranasal insulin will provide important preliminary data to evaluate the sample 
size needed for a larger study of efficacy. 
Pharmacokinetics outcome measures/endpoints and analysis 
PK protocol data will include ARV drug levels and insulin levels. Analysis of PK data will include the 
generation of concentration-time data for insulin and ART drugs using commercial software (PK solutions, 
Summit Research Services, Montrose, CO; WinNonlin, Pharsight, Cary, NC). Non-compartmental analysis 
will be used to estimate Cmax, Tmax, ALIC, CL/F, V/F, and half-life where possible given drug 
pharmacokinetics and 24 hour dosing intervals. Comparison of antiretroviral pharmacokinetics before and 
after the addition of insulin will be assessed using geometric mean ratio with 90% confidence intervals of 
pre-dose drug levels at baseline and those at both 1 week and 4 weeks after initiating insulin. 
Toxicity management/assessment of safety and adverse events 
The procedures used in Adult AIDS Clinical Trial Group (ACTG) HIV neurology studies will be used for 
management of study drug related toxicities. The study drug may be decreased to 50% of the daily dose 
twice a day or suspended to assess/treat clinical or laboratory adverse experiences.  If after 1 week, the 
adverse experience leading to the temporary holding of the study drug improves sufficiently, the subject may 
be rechallenged at 50% of the daily dose regimen for 1 week (intranasal insulin 20 I U a day or matching 
placebo) or full dose study drug if the initial dose reduction was decreased to once daily.  If the clinical or 
laboratory adverse experience does not occur again on the 50% of the daily dose regimen for 1 week, then 
the full daily dose regimen may begin.  If the adverse experience recurs, the treatment may be suspended 
again for 7 or more days, and the subject may be re-challenged.  If there is no improvement in the adverse 
experience with ≥ 31 day treatment suspension, the subject must be permanently discontinued from study 
treatment.  The toxicity grading system of the ACTG will be used to characterize toxicity severity. 
 
Data Safety and Monitoring Plan 
The clinical trial will be monitored by a Data and Safety Monitoring Board (DSMB) led by Dr. David 
Clifford (Washington University-St. Louis). He will interact with the other 2 members of the board and 
review semiannual closed and open reports provided to him by the PI (blinded) and site pharmacist 
(unblinded). Unblinded data will not be made available to non-DSMB members. After discussion by the 
DSMB members, they will present their recommendations to project investigators, and the study team will 
forward the reports, as requested, to the IRB.  Enrolled participants will be monitored throughout the 
study for untoward incidents (e.g., “Adverse Events”) occurring during the study. The Principal 
Investigator (and other designated individuals, if necessary) will conduct regular monitoring for 
safety concerns and provide general oversight for human safety requirements. Where necessary 
these occurrences will be evaluated for severity, attribution, and possible trends. All adverse events 
that are anticipated or described in the informed consent form will be logged appropriately and 
reported to the IRB on at least an annual basis (e.g., at continuing review). Any Unanticipated 
Problems or unexpected “Serious Adverse Events” related to the study intervention and/or test 
article and affecting the risk/benefit profile of the study, will be reported to the IRB promptly, and, 
in all cases, within 10 business days of discovery. Unplanned and non-emergent deviations from the 
IRB approved protocol will be logged and reported to the IRB annually at continuing review; all 
planned deviations will be submitted as a Change in Research to the IRB for approval prior to 
implementation. FDA (IND) and NIH reporting requirements will be followed, and all required 
institutions will be notified of events/problems encountered in the study and/or changes in research, 
in accordance with all applicable regulations and guidelines. 
 

 
 
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8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
b. Steps taken to minimize the risks. 
c. Plan for reporting unanticipated problems or study deviations. 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
e. Financial risks to the participants. 
 
Safety of Intranasal Insulin  
Safety issues pertaining to intranasal insulin administration for the treatment of diabetes have been 
extensively explored for over two decades (93). The most common side effects associated with intranasal 
insulin from the recent study for Alzheimer’s disease (19) were lightheadedness/dizziness (13.2%), runny 
nose (rhinitis) (7.0%), headache (5.3%), nosebleed (2.6%), upper respiratory tract infection (2.6%), falls 
(2.6%), and rash (2.6%) using the 40 IU/day dose of insulin proposed for the current study. There was no 
difference in the frequency of any of those specific adverse events in the insulin 40 IU group and the placebo 
group.  In addition, there were no severe adverse events in the study (19). Anaphylaxis has not been seen 
with intranasal insulin, but has been observed rarely with other routes of administration. A recent safety 
study of intranasal insulin administration demonstrated no treatment induced changes in blood glucose 
levels, nasal airway patency, or transnasal pressure gradient (94). 
Regarding the risk of hypoglycemia, at least five peer reviewed human studies (94-98) (submitted for 
publication) and four preliminary studies (19, 99-101) revealed no change in blood glucose levels following 
intranasal insulin administration with doses that included 40 IU 4 times daily for two months. There was one 
exception with the case of a single participant who experienced mild hypoglycemia (52 mg/dl) after skipping 
a meal and engaging in sustained vigorous exercise. 
In addition, a recent safety study (94) examined intranasal insulin administration of 60 IU once a day for 
three weeks in 20 healthy adults. This randomized, double-blind, placebo-controlled crossover trial measured 
blood glucose levels six times a day during the first two and the last two days of treatment. Pre- and post-
treatment blood laboratory tests and nasal examinations were performed. The nasal studies included 
rhinoscopy to detect local irritation, a saccharin particle test to analyze mucocilary clearance, and 
rhinomanometry to evaluate nasal airway patency and transnasal pressure gradient. Results indicated no 
change in blood glucose values with insulin, and no change in the frequency of glucose values above 3.0 
mmol/L. The only symptomatic hypoglycemic value occurred during placebo treatment. Insulin treatment 
had no effect on other laboratory values (C-peptide, total cholesterol, HDL, LDL, triglycerides, creatinine, 
glutamyl transferase), blood pressure, or body weight. Nasal examinations revealed no adverse effects or 
functional disturbances following intranasal insulin administration. No serious adverse effects of treatment 
were observed in the preliminary studies (19, 99, 100, 100). 
There are no known serious risks associated with intranasal insulin without absorption enhancers. One 
industry report raised the issue of rare but significant increases in lung cancer in smokers treated with inhaled 
insulin; six of 4740 patients taking inhaled insulin developed lung cancer compared with one of 4292 
patients who received an active comparator (incidence per 100 patient year exposure, 0.13 vs 0.02). 
However, the inhaled insulin protocol used for diabetes treatment in this report included absorption 
enhancers to maximize delivery to lungs, whereas the nose-to-brain delivery device to be used in this study 
greatly minimizes lung delivery without using absorption enhancers. 
There are fewer safety data for intranasal insulin use by patients with HIV infection and it is possible that 
long-term administration may induce CNS hyperinsulinemia or insulin resistance that may have deleterious 
effects. Such effects would presumably manifest as accelerated cognitive or functional decline. Thus an 
intensive safety-monitoring plan will be in place for this study that should detect such patterns and a 
conservative duration of treatment will be used that balances safety and scientific considerations.   
 
 

 
 
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Risks associated with use of the POD® device  
Although not expected to be serious, there are risks that may occur from using the investigational intranasal 
drug administration device (POD®). It is important that participants carefully follow the instructions they are 
given about how to administer the study drug and how to clean the device. If they do not carefully follow the 
instructions, it is possible that they may not receive the correct dose or the device may become contaminated. 
Participants could experience some discomfort to their eyes or face if they do not hold the device to their 
nose as directed. There may also be risks associated with intentional misuse of the device to administer 
unapproved drugs or substances. The study team will train the participant on proper device operation prior to 
starting the clinical trial and monitor technique and device function throughout the trial.  
 
Risks lumbar puncture 
Risks to lumbar puncture include post-lumbar puncture headache, back pain, minor neurologic symptoms 
such as numbness or pain radiating down a leg, allergic reaction to the medication used for numbing the 
lower back (rare), bleeding into the spinal cord (rare), infection (rare), cerebral herniation (rare). 
About 10% to 30% of people develop a headache after LP. These headaches typically affect the front or back 
of the head and happen within 24 to 48 hours of the LP. The pain is usually worse when standing or sitting 
upright and improved when lying down flat. For some people a post-LP headache may be bad enough to 
limit daily activity. 
To lessen the risk of post-LP headache, we use a thin 22 gauge needle for the procedure (rather than the 20 
gauge needle also commonly used) and ask participants to lie flat for at least 30 minutes immediately 
afterward. We also strongly advise the participants to continue to rest at home and avoid difficult physical 
activities for at least a day or two, as well as drink plenty of fluids following the procedure. In the event of a 
post-LP headache, we may prescribe anti-inflammatory medicine as needed, or recommend common over-
the-counter anti-inflammatory medicine. If the post-LP headaches last for more than 2 to 3 days and are not 
helped by anti-inflammatory medications, we may recommend that the participant undergo an epidural blood 
patch procedure in which the participant’s own blood is injected into the same area of the original LP. We 
will not perform this procedure as part of the study, but we can refer the participant to a doctor who can. 
While uncommon, sometimes during the LP procedure people experience a brief, sharp pain (often described 
as “electricity”) that radiates into the lower back, buttock, or leg on one side. This is a temporary sensation 
and does not indicate nerve damage. Nerve damage with permanent loss of muscle power, sensory function 
(ability to feel), or bowel or bladder function from LP is extremely rare. Most people have some mild back 
pain or soreness after the LP around the site of injection. This pain usually goes away within a day or two. 
Prolonged back pain greater than three days is uncommon. People with a history of back problems may have 
a greater risk of prolonged or severe pain after the LP.  
A small percent of people are allergic to local anesthetics used to numb the skin during the LP. We typically 
use lidocaine (chemically similar to novocaine). An allergic reaction to this medicine could include itching, 
hives, swelling, shortness of breath, difficulty breathing, changes in blood pressure and heart rhythm, loss of 
consciousness, or in a rare case, death. 
Serious bleeding that affects the spinal cord is an extremely rare but dangerous complication. It is primarily a 
risk for people who have very low blood platelet counts (thrombocytopenia) or other bleeding disorders, or 
for those who are taking anticoagulant therapy (for example coumadin or warfarin) prior to or immediately 
after the LP. We perform safety blood tests to make sure participants are not at significant risk of this 
complication. We will not perform the LP if the participant is shown to have a serious coagulation defect, a 
platelet count under 50,000/µL, or a blood INR greater than 1.4. 
Infection during the LP is extremely rare. We perform the procedure using sterile techniques to avoid this 
complication. Another serious but extremely rare complication that can occur during the LP is cerebral 
herniation (brain swelling). This is primarily a concern for people in emergency situations who have 
increased intracranial pressure (ICP). Participants with any signs or symptoms of increased ICP will not 
receive an LP. 
If abnormal findings are found as a result of the lumbar puncture analysis, we will refer the participant to 
their primary healthcare provider for further testing and treatment. If the findings are critically urgent, we 
will refer the participant to the Johns Hopkins Hospital Emergency Department. 

 
 
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Risks of Magnetic Resonance Imaging (MRI) 
The effects of magnetic fields in an MRI scanner have been extensively studied, and there are no known 
significant risks with an MRI exam. Participants may be bothered by claustrophobia and by the noise made 
by the magnet during the procedure. Participants will wear earplugs or earphones while in the magnet. 
Participants will not receive an MRI if they have a pacemaker, an implanted defibrillator or certain other 
implanted electronic or metallic devices, history of brain surgery for a cerebral aneurysm, or history of 
shrapnel or other metal in the body (e.g. eye injury) without history of recent MRI or screening X-ray. 
There are also risks associated with an incidental finding from the MRI exam. In general, the possibility or 
identification of an incidental finding may cause anxiety. Costs for any care that will be needed to diagnose 
or treat an incidental finding would not be paid for by this research study. These costs would be the 
participant’s responsibility. The incidental finding will be part of the participant’s medical record, and there 
is the potential risk that the participant could face greater difficulty in getting health or life insurance.   
Risks of clinical and neurological procedures 
The risks to participants from the neurological and neuropsychological evaluations and medical interview are 
minimal. Occasionally, neurological examination or neuropsychological test administration may induce 
anxiety, or blood tests and urine screening may provoke concern if they reveal a condition unexpected by the 
participant. Anxiety is usually controllable with appropriate counseling and explanation by the study team, 
and if appropriate, the study team may coordinate care with the participant’s primary care provider to address 
medical concerns that he/she may have. 
The risks of venipuncture include needle entry discomfort and bruising, and rarely infection. Possible 
complications from peripheral IV lines for blood draw include phlebitis, bruising, and hematoma formation. 
According to Up-to-Date: “thrombophlebitis occurs in up to 15 percent of those with peripheral venous 
catheters. This risk can be reduced by avoiding lower extremity IV placement, minimizing catheter 
movement, placing the smallest suitable catheter size, and removing the catheter as soon as possible.” (Frank, 
RL. “Peripheral venous access in adults,” Up-to-Date, Topic 13824 Version 12.0, accessed 8/3/2017)Risks 
to subject’s privacy 
There is the risk of loss of privacy by joining this study. The investigators will do everything possible to 
minimize the risk. Any PHI collected for this study will be kept confidential through the use of a secure, 
double-lock office storage space and an encrypted, password-protected computer database. Biosamples will 
be stored in double-lock protected laboratory freezers; labels will include unique subject and specimen ID 
numbers and no personal names or identifiers. 
 
Financial risks 
The costs for the procedures, tests, drugs or devices that are part of this research will be paid for by the study. 
Participants are responsible for all other healthcare costs that may occur outside of the events and procedures 
we conduct in our protocol whether related to the study or not. If the participant has health insurance, he/she 
will be responsible for any co-pays or deductibles not covered by insurance. 
If the participant cannot pay the costs that are his/her responsibility, the participant may request a financial 
hardship review. This would be done according to standard Johns Hopkins guidelines. Information about 
where and how to request a financial hardship review will be provided in the Insurance and Research 
Participant Financial Responsibility Information Sheet and in any bills received from Johns Hopkins. If the 
participant qualifies for financial hardship, the costs to the participant will be reduced. Taking part in this 
study may lead to added costs to the participant and his/her insurance company. In some cases, it is possible 
that the participant’s insurance company will not pay for these costs because he/she is taking part in a 
research study. 
 
 

 
 
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9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
There is no expected direct benefit to volunteers in this study. The potential benefit to the participant and for 
society is that the study may provide preliminary data for an effective adjunctive therapy for the treatment of 
HIV associated neurocognitive disorder (HAND). 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. 
 
Subjects will receive $50 for completion of the screening, week 12, and week 24 visits, and $100 for the 
lumbar puncture at the pre-entry visit and week 24 visit. Subjects will receive $20 for completion of the week 
1, 4, 8, 16, and 20 visits. Subjects will also receive $50 for the MRI scan at baseline and week 24. Travel to 
and from the clinic by taxi will be arranged by the study team, or each participant will receive up to $20 per 
visit to cover transportation costs. 
Participants who complete the optional PK protocol will receive $10 for the extra CSF drawn at pre-entry 
and $10 for each extra amount of blood drawn at the baseline, week 1 and week 4 visits. Participants will 
receive $100 at the week 12 visit for the sum total of serial blood samples drawn, and $100 for the additional 
LP at week 12. 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 
 
There will be no costs to the participants for the study procedures or study drug. Management of any adverse 
events resulting from study procedures will be performed through the participant’s routine care and 
reimbursement services. (See Section 8, Financial Risks) 
 

 
 
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Appendix A 
 
Table 1. 
Schedule of Lab Tests
Visit: Screen
Pre-
Entry 1
Pre-
Entry 2
D000 
(Baseline) D007 D028 D056 Midtrial D112 D140 Final 1 Final 2 Ad Hoc
Timeline (days): -45 to -1 -21 to -1 -14 to -1
Day 0
7 ±3 28 ±3 56 ±3
84 ±3
112 
±3
140 
±3
161 to 
175
161 to 
182
-45 to 
182
Blood Tests
Complete Blood Count (CBC)
X
X
X
X
X
X
X
[X]
Comp Metabolic Panel (CMP), non-fasting
[X]
CMP, fasting for glucose
[X]
Glucose, fasting
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
Insulin, fasting
X
X
X
X
X
X
[X]
[X]
Amylase/Lipase
X
[X]
X
[X]
T-cell Subset
X
X
X
X
X
X
X
[X]
HIV RNA Viral Load
X
X
X
X
X
X
X
X
[X]
PT/aPTT
[X]
[X]
[X]
[X]
HIV ELISA (if needed)
[X]
Thyroid Stimulating Hormone (TSH)
X
[X]
Syphilis/RPR
X
[X]
Vitamin B12
[X]
Hepatitis C testing
[X]
Repository, Blood
X
X
X
(X)
X
X
X
X
X
X
[X]
[X]
CSF Tests (LP Optional)
Protein/Glucose, CSF
(X)
(X)
Cell Count w/ Diff, CSF
(X)
(X)
Repository, CSF
(X)
(X)
Key: 
X
[X]
(X)
v.18.09.26
Lab test/procedure to be performed as needed
Lab test/procedure is optional
X
X
[X]
X
Intranasal Insulin for the treament of HAND (IRB00108564)
Scheduled lab test at visit per protocol
X
X
X
X
X
One or the other lab test scheduled at visit
X
(X)
Single lab test required within range of visits
(X)
(X)
X
X
X
X
X
X
X
[X]