iSTEP - an mHealth Physical Activity and Diet Intervention for Persons With HIV
Phase: NA
Conditions: HIV/AIDS
Sponsor: University of California, San Diego

 
 
 
 
 
 
Study Protocol and Statistical Analysis Plan 
 
Title of Study: iSTEP - an mHealth Physical Activity and Diet Intervention for Persons With 
HIV 
 
NCT: NCT03123731 
 
Date of Document: 12-1-2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 

 
3 
 
 
CONTENTS 
 
 
Page 
 
ABSTRACT ..................................................................................................................................... 4 
SCHEMA ....................................................................................................................................... 5 
1.0 
INTRODUCTION ............................................................................................................... 6 
2.0 
STUDY DESIGN ............................................................................................................... 8 
3.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................... 8 
3.1 
Inclusion Criteria .................................................................................................... 8 
3.2 
Exclusion Criteria .................................................................................................. 9 
4.0 
CLINICAL MANAGEMENT ISSUES ................................................................................. 9 
4.1 
Adverse Events ..................................................................................................... 9 
4.2 
Clearance from Primary Physician ...................................................................... 10 
5.0 
STATISTICAL ANALYSIS PLAN .................................................................................... 11 
5.1 
Analyses .............................................................................................................. 11 
5.2 
Power Analyses ................................................................................................... 12 
6.0 
PARTICIPANTS .............................................................................................................. 13 
 
6.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 13 
6.2 
Participant Confidentiality .................................................................................... 13 
6.3 
Study Discontinuation .......................................................................................... 13 

 
4 
 
 
 
 
ABSTRACT 
 
People who live with HIV (PLWH) experience a high incidence of neurocognitive deficits and 
HIV-associated non-AIDS (HANA) disorders, including cardiovascular disease (CVD), metabolic 
dysfunction, and autonomic decline. While antiretroviral treatment (ART) has reduced AIDS-
related morbidity, both the virus and the medications are associated with lipid disorders that also 
increase CVD risk, including dyslipidemia and lipodystrophy. Consequently, the development of 
effective lifestyle interventions to reduce the incidence of HIV-associated neurocognitive 
disorders (HAND) and decrease metabolic disorders is a high priority. Physical activity (PA) has 
been utilized as an effective tool to improve health in PLWH, but may not be sufficient by itself 
to improve lipid levels. Existing PA interventions in PLWH typically required strenuous PA and 
significant resources that limit feasibility for many people living with the disease. Recent work 
indicates that interrupting periods of sedentary behavior (SB), independent of PA, also has a 
significant beneficial effect on metabolic function, but SB has not been well-studied in PWLH. 
Mediterranean-style diets (MedDiet) are also effective at improving CVD risk factors in HIV-
uninfected individuals and are reported to reduce cognitive decline in persons at risk for 
Alzheimer’s disease, but have not been widely tested in PWLH. We recently developed a novel 
and personalized Short Message Service (SMS) mobile phone text messaging intervention 
(iSTEP) that is designed to increase moderate PA in PLWH. Our objective is to expand upon 
this work and conduct an RCT examining the efficacy of iSTEP in combination with a mobile 
mHealth MedDiet intervention tailored to PLWH. 150 PLWH will be randomly assigned to a 
control group (n = 50), a 6-month iSTEP group with just a PA/SB intervention (n = 50), or a 6-
month intervention with both PA/SB and MedDiet components (n = 50), where participants 
receive daily interactive SMS/MMS messages designed to increase moderate PA, reduce SB, 
and promote adherence to a MedDiet, including walnut consumption. PA/SB will be quantified 
by accelerometer, Fitbit step counts, and self-report, while MedDiet adherence will be assessed 
by self-report (Diet History Questionnaire and weekly SMS feedback) and also objective 
measures (polyunsaturated fatty acid levels - PUFA in blood). We will also conduct a follow-up 
assessment 6 months after the end of the intervention (accelerometer, neurocognitive testing, 
PUFA levels) to assess PA and MedDiet adherence. We hypothesize that iSTEP (both 
intervention arms) will increase PA, reduce SB, and improve neurocognition compared to 
control; the iSTEP + MedDiet group will demonstrate improvement in CVD risk factors and 
neurocognition compared to the PA intervention alone. Findings from this proposal will lay the 
groundwork for development of novel large-scale mobile PA/diet interventions dedicated to 
treating HAND and improving cardiovascular health for PLWH.  

 
5 
 
  
  
 
 
 
 
SCHEMA 
 
iSTEP - an mHealth Physical Activity and Diet Intervention for Persons With HIV 
 
DESIGN: Our objective is to assess the efficacy of a mobile phone text message intervention 
(iSTEP) designed to increase moderate physical activity (PA), reduce sedentary behavior (SB), 
and improve diet in people living with HIV (PLWH) in order to improve neurocognitive function 
and reduce cardiovascular disease (CVD) risk. This is a randomized RCT where participants 
are enrolled into one of three conditions: 1) a Control Group; 2) a PA intervention; 3) a PA + 
Diet intervention focused on encouraging a Mediterranean-style diet (MedDiet). 
 
POPULATION: PLWH  
 
STRATIFICATION: none 
 
REGIMEN OR INTERVENTION  
Assignment to 24-week control group, PA intervention, or PA + Diet Intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
6 
 
  
  
 
 
 
 
1.0 
Introduction 
 
HIV-associated neurocognitive disorders (HAND) remain a significant problem for PLWH and 
are linked to metabolic and cardiovascular disorders. Approximately 30-60% of persons living 
with HIV (PLWH) manifest some form of neurocognitive impairment, including deficits in 
executive function, attention, and memory collectively referred to as HIV-associated 
neurocognitive disorders (HAND)1. Growing evidence indicates that metabolic syndrome (MetS) 
is an important factor that increases the risk and severity of neurocognitive impairment (NCI) in 
PLWH. MetS is frequent in PLWH, reported to be present in 47% of 2247 individuals during a 3-
year period of participation in an AIDS Clinical Trials Group RCT study25. MetS also increased 
the odds of neurocognitive decline in a sample of 643 PWLH patients with assessments at 6-
month intervals26. NCI severity in PLWH correlates with waist circumference (WC), a measure 
of abdominal obesity27. Despite the efficacy of antiretroviral therapy (ART), PLWH continue to 
experience excess levels of morbidity and mortality linked to HIV-associated non-AIDS (HANA) 
disorders, including cardiovascular disease (CVD), metabolic dysfunction, and autonomic 
decline6, 7, 28. CVD is now emerging as a major non-AIDS complication, with up to 20% of HIV+ 
individuals exhibiting a moderate to high 10-year risk of myocardial infarction (MI)29. 
Contributing factors to CVD and MI risk include a pattern of lipid abnormalities, including 
increased serum triglycerides, lower high-density lipoprotein cholesterol (HDL-C), and higher 
low-density lipoprotein (LDL) cholesterol30. PLWH also exhibit impaired autonomic nervous 
system (ANS) function indicated by decreased heart rate variability (HRV), a marker of poor 
vagal tone predictive of future CVD complications and higher rates of mortality31, 32. While 
healthy individuals exhibit a high degree of HRV, reflecting the ability of the ANS to adapt 
quickly to physical or psychological challenges in the environment33, reduced HRV persists in 
virus-suppressed PLWH taking ART and is linked to hypercholesterolemia34, 35. CVD risk is also 
clearly increased by the use of ART itself, with a reported 26% relative increase in MI per year 
of ART exposure during the first 4-6 years of use36. In summary, HAND, MetS, and elevated 
CVD risk are closely related and remain prevalent in PLWH; there is thus a significant unmet 
need to find effective strategies to address these ongoing issues5. 
 
Physical Activity (PA) may provide many benefits for PLWH. PA provides a myriad of health 
benefits, including treating cardiometabolic disorders and improving HRV in persons with CVD, 
pulmonary disorders, and obesity37-39. Previous work in younger PLWH has shown that aerobic 
and resistance PA interventions improve fitness, reduce body fat, and normalize the lipid 
profile40, 41. However, these studies involve rigorous PA conducted at gym facilities, a 
methodology that is not widely feasible for HANA treatment in PLWH with frailty and limited 
resources8-10, 42. Although strenuous PA may not be suitable for many PLWH, increasing 
moderate PA, including walking, has significant health benefits and may improve metabolic and 
autonomic function43-46. For example, increasing step counts by 2,000-3,000 a day decreases 
total cholesterol47, less than 3 hours of light PA per week reduces mortality for subjects with 
metabolic syndrome48, and low-intensity walking also improves HRV39, 49. CVD risk may be 
significantly reduced by modest lipid changes, e.g., increasing HDL-C by 5 mg/dL, reducing 
LDL-C by 10 mg/dL and triglycerides by 40 mg/dL, or lowering percent body fat by 1% and BMI 
by 1 kg/m2 50, 51; these effects can be achieved by moderate PA such as walking in HIV-
uninfected persons52. However, exercise interventions in PLWH have also reported that PA may 
not improve lipid levels in a population challenged by both the virus and harmful side effects of 
ART23; these data suggest that an intervention approach that targets multiple modalities (PA, 
diet) may be more optimal. 
 
Sedentary behavior (SB) is not well-characterized or addressed in PLWH. Sedentary behavior 

 
7 
 
  
  
 
 
 
 
(SB), defined as sitting or reclining during waking hours with low energy expenditure (1.0 to 1.5 
metabolic equivalents), is a distinct construct from PA and has recently been identified as a 
significant contributor to all-cause mortality, increased CVD risk, and poor metabolic function14, 
53-55. While moderate PA may occur during a small proportion of the day, adults in developed 
countries spend 55-70% of their time engaged in SB54. Both the quantity and duration of SB 
intervals are related to metabolic health and have adverse cardiometabolic consequences even 
for physically active individuals14-16, 54, 56-59. Every hour of daily sitting time is associated with a 
2% increase in all-cause mortality, with a jump to 5% for sitting 7 or more hours per day60. 
However, simply interrupting periods of SB, even with very short intervals (a break of 60 
seconds or more) with light PA (standing, walking a few feet) has demonstrated benefits for 
metabolic function, including improvements in triglyceride levels, HDL-C, glucose metabolism, 
and insulin sensitivity43, 53, 55, 58, 61-63. Unfortunately, SB has not been well-characterized in PLWH 
and little work has been done to modify this behavior in this population. 
 
A Mediterranean-style diet (MedDiet) that includes walnut consumption may benefit both CV 
function and neurocognition. PLWH are reported to have poor diet quality, including higher fat 
consumption and lower fiber intake compared to HIV-uninfected individuals64, 65. Several diet 
interventions focused on reducing saturated fat intake are reported to improve the lipid profile 
(reducing triglycerides, total cholesterol, and LDL-C levels) 66-69, including significant 
improvements within a 6-month timespan66, 68. However, limited changes have been observed 
for HDL-C, potentially resulting from an emphasis on reducing saturated fat (a traditional low-fat 
diet), but not on increasing exposure to polyunsaturated fats, in line with a MedDiet approach19. 
The primary MedDiet objectives include consumption of monounsaturated and polyunsaturated 
fat sources, fruits and legumes, and whole grains70, including: 1) 3 or more servings of fish and 
seafood per week (a serving is generally equivalent to ½ to 1 cup of food); 2) 3 or more servings 
of nuts or seeds per week; 3) virgin olive oil for cooking (> 1 spoonful/day); 4) selected white 
meat (poultry); 5) fruit and vegetables (> 1 serving per day); 6) 2 or more servings of legumes 
per week; 7) whole grain breads. Eating white bread, white rice, red meat, processed pastries, 
cream and butter is discouraged. A large 12-month MedDiet study (PREDIMED) (7 years and 
8000 participants71) randomized persons into 3 groups: a low-fat diet condition, a MedDiet group 
with an emphasis on virgin olive oil (VOO) intake, and a third MedDiet group with daily nut 
consumption (1 ounce per day of nuts, including walnuts). MedDiet administration led to many 
benefits, including: 1) a 30% reduction in CVD incidents for the MedDiet groups compared with 
the low-fat control72, 73; 2) decreased oxidative stress74, 75; 3) lower risk for CVD events 
generated by abdominal obesity76; 5) improved cognition compared to the low-fat diet (Mini-
Mental State Examination and Clock Drawing Test)77. Importantly, other studies demonstrate 
that MedDiet improves metabolic function (lower cholesterol, triglycerides) after only 3 months78.  
 
Polyunsaturated fatty acids (PUFA), and omega-3 PUFA (n-3 PUFA) from sources such as 
walnuts may have significant benefits for brain health and cognition79. Walnuts contain high 
levels of α-linoleic acid (ALA), which is converted to PUFAs such as eicosapentaenoic acid 
(EPA) and docosahexaenoic acid (DHA). These PUFAs contribute to brain health via several 
mechanisms, including stimulating neurogenesis, improving energy transport to the brain, 
reducing inflammation, and activating brain-derived neurotrophic factor (BDNF)80, 81. 
Administration of walnuts (80 mg/day) to rats for 4-8 weeks improved cognitive performance on 
a radial arm water maze82, with optimal performance observed with a 6% walnut diet, equivalent 
to 1 ounce of daily walnut intake in humans (as with PREDIMED)79. Nut consumption was also 
associated with improved working memory and reduced stroke risk in the PREDIMED cohort83. 
Administration of n-3 PUFAs for 6 months also reduced cognitive decline in patients with 
Alzheimer’s disease81, 84, 85.Finally, preclinical studies indicate that combining PA and n-3 

 
8 
 
  
  
 
 
 
 
PUFAs may optimize cognitive improvement; DHA supplements enhanced the beneficial effects 
of exercise in rats (12 days) on cognition and BDNF-related synaptic plasticity86; one week of 
exercise in rats combined with n-3 PUFA treatment increased markers of synaptic plasticity and 
glutamate receptor expression beyond either condition alone, biomarkers that correlated with 
improved performance on the Morris water maze87. In summary, these findings suggest that a 
MedDiet approach augmented with walnut consumption, in combination with PA, may 
successfully reduce CVD risk and neurocognitive deficits in PLWH. 
 
mHealth interventions improve PA and diet. Mobile health (mHealth) text messaging 
interventions have promoted a variety of health behaviors, including increasing PA and reducing 
body fat and cholesterol over periods as short as 12 weeks88 89-91. Although Short Message 
Service (SMS) protocols have been developed to improve medication adherence in PLWH92, 93, 
this methodology has not been utilized to promote PA or diet interventions in this population. In 
addition, few studies have specifically targeted SB in PLWH94. Participant feedback has focused 
on three themes: adding a competitive component to iSTEP (allowing participants to compare 
their PA with others), being able to track their SB, not just steps, and the inclusion of diet as part 
of the intervention. Here we propose to conduct an mHealth intervention that examines the 
efficacy of a PA/SB intervention alone compared to PA/SB + MedDiet condition designed to 
improve neurocognitive performance and reduce CVD risk in PWLH with HAND and metabolic 
syndrome. 
 
 
2.0 
STUDY DESIGN  
 
We will recruit 170 community-dwelling PLWH (20 for focus groups, 150 for the RCT) using the 
services of the UCSD HIV Neurobehavioral Research Program (HNRP) and the associated 
NIMH-funded HIV Neurobehavioral Research Center (HNRC) (P30 MH062512) and the 
Translational Methamphetamine AIDS Research Center (TMARC) (P50 DA026306). These 
centers have supported numerous multidisciplinary endeavors among PLWH over the past 20+ 
years and facilitate PLWH recruitment from the San Diego area and comprehensive 
neuromedical testing. While we will include participants who have previously engaged in 
research studies at the HNRP, we will also use our community outreach facilities to recruit 
PLWH who have not previously participated in research; this approach will enable a more 
appropriate representation of the general population and maximize the number of available 
participants. Recruitment and testing will be facilitated by an extensive research team.  
 
 
3.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
3.1 
Inclusion Criteria 
 
3.1.1.  Ability of participant to provide informed consent. 
 
3.1.2   Age 18 or older. 
 
3.1.3   HIV infection documented at the University of California, San Diego (UCSD) HIV 
Neurobehavioral Research Program (HNRP) or assessed by an HIV test at 
screening  

 
9 
 
  
  
 
 
 
 
 
3.1.4    proficient in English 
 
3.1.5   Physically capable of participating in moderate PA as screened by the Physical 
Activity Readiness Questionnaire 
 
3.1.6    Consent from primary care physician to participate in the study 
 
3.1.7   Able to consume walnuts - no nut allergies 
 
3.2 
Exclusion Criteria 
 
           3.2.1.  Any physical conditions that would prevent moderate physical activity or where 
moderate physical activity would represent a health risk for the individual, 
including a history of myocardial infarction or stroke           
           3.2.2  Unwillingness or inability to participate in daily text messaging 
           3.2.4.  Tree nut allergy that would prevent walnut consumption or other food restrictions 
that would prevent participation in the Mediterranean-style diet intervention (e.g., 
unable to eat fish or use olive oil for cooking). 
 
 
 
4.0 
CLINICAL MANAGEMENT ISSUES 
 
4.1 
Adverse Events  
 
We have taken great care to minimize the risks associated with text messaging in this study, 
including eliminating any information in the SMS content that could identify the HIV status of the 
participants. For example, we will not use any medication names in messages (e.g., identifying 
an HIV medication) or include content that could be used by a third party to identify a particular 
medical condition, but will utilize generic messages that ask about relevant physical conditions 
and limitations (e.g., do you have muscle aches today?). We will not include any personally 
identifiable information such the name of the participant in the SMS content sent to each subject 
or stored on mobile phones provided to participants. Text messages will include geographical 
landmarks such as nearby locations to engage in PA or the names of specific grocery stores to 
purchase food items; there is a risk this information could be accessed by an unauthorized 
person if the cell phone is lost or stolen. 
 
Participants may experience anxiety or embarrassment related to one’s personal PA or diet 
behavior (e.g., a lack of physical activity) or feelings of inadequacy with limited progress during 
the intervention. Participants in the focus groups may experience nervousness from 
participating in a group process activity or speaking in front of others regarding the issues that 
may affect PA or diet. Participants will be motivated to engage in moderate PA, including 
walking, and light PA to reduce and interrupt SB. No vigorous PA will be required. Some 
participants may experience mild muscle fatigue or soreness. Standard clinical interview 
procedures, including administration of PA and diet questionnaires, pose little risk to 

 
10 
 
  
  
 
 
 
 
participants.The blood draw procedure includes the risk of minor discomfort, bruising, fainting, 
or dizziness.  
 
As with any HIV study, one potential risk is that of breach of confidentiality wherein a person's 
HIV status, sexual behaviors, or other sensitive information might be disclosed, resulting in 
embarrassment or prejudicial treatment by others. We will adhere to the standard risk 
management protocol in this regard, including use of participant identification numbers, locked 
data cabinets, and password protected computer databases. To ensure confidentiality, only the 
participant's code number will appear on all data forms as is standard at the HNRP. All paper-
based records, forms, and data are kept in a locked interior file room. All medical records and 
demographic data also are locked in file cabinets within the file room. Computer records are 
protected by standard measures that limit access to the data to selected research project 
personnel. The electronic data are protected by multiple levels of password access, including to 
individual machines, the server, and to the central database. An HNRP Confidentiality 
Committee performs regular inspections to monitor procedures. In addition, the HNRP is 
protected from subpoena of confidential records by a Federal Certificate of Confidentiality. 
 
 
4.2 
Clearance from Primary Care Physician  
 
Participants will be excluded for any physical conditions that would prevent moderate PA or 
where moderate PA would represent a health risk for the individual, including a history of 
myocardial infarction or stroke, pain in the chest when exercising, chronic joint problems 
aggravated by exercise, or a history of falls or balance problems. To minimize the probability of 
adverse events, participants will be screened for medical conditions using the Physical Activity 
Readiness Questionnaire; any indication of physical conditions that preclude moderate PA will 
result in the exclusion of the participant from the study. As an additional safeguard, each 
participant’s PCP will be contacted, with participant consent, to verify if there are any medical 
issues that would prevent involvement in this study. Study personnel will initially contact the 
physician by phone, after receiving written consent from the participant, to determine if the PCP 
is willing to provide medical clearance for the intervention. If the participant’s doctor agrees to 
do so, we will mail the PCP a medical clearance form that describes the SMS study and lists the 
options for moderate PA, such as walking, household activities (e.g., gardening). The form will 
provide the physician with the option to endorse study participation, deny participation due to 
known risks, postpone clearance contingent on further medical assessment, or acknowledge 
that they lacked adequate knowledge of the patient’s medical history to make an informed 
decision. The form will also allow the PCP to indicate that some activities, but not others are 
appropriate for the patient (e.g., walking is acceptable, but not climbing stairs). If the participant 
is enrolled, this information will be incorporated into the SMS prompts they receive. We will 
request that the PCP mail the completed form back to the PI. Participants will not be permitted 
to start the intervention until this written medical clearance is received. If the participant reports 
an adverse event or contraindication to moderate PA during the intervention (e.g., muscle 
soreness, shortness of breath), he or she will be suspended from the study until written medical 
clearance is again provided by the PCP. This will involve a second medical clearance form that 
will describe the adverse event and allow the PCP to indicate if the individual can resume the 
program, should discontinue, or if more evaluation is needed. 
 
Ongoing medical treatment for HIV will not be altered or modified in any way for research 

 
11 
 
  
  
 
 
 
 
purposes. All subjects will be provided with PA safety and injury prevention recommendations 
before beginning the study, including instructions on warming up and stretching activities. 
Participants will be counseled that it is appropriate to gradually increase their PA (e.g., increase 
step counts by 10% per week) to reduce the risk of musculoskeletal injury and adverse events. 
During the initial enrollment and screening process, participants will be asked to phone the PI if 
any adverse events occur during study participation. In an emergency situation where 
participants are in need of immediate help as a result of an adverse event, the participants will 
be informed that they should first call 911 and then report the incident to the study staff as early 
as possible. Participants will also be contacted by telephone on a monthly basis by the PI to 
inquire about any adverse events, including chest pain, dizziness, or falls. Subjects will also 
receive regular text messages that will solicit information about any adverse events associated 
with their PA and any affirmative responses will be received by the PI who will contact the 
participant. In the case of any adverse events, participant PA activities will be immediately 
discontinued and the subject’s PCP will be contacted to coordinate appropriate evaluation and 
treatment. Participant text logs will be monitored on a daily basis to ensure that no serious 
problems have occurred and to supervise each individual’s continuing participation in the study. 
Participants are informed that they may withdraw from the research at any time if they find any 
aspect objectionable. 
 
 
5.0 
STATISTICAL ANALYSIS PLAN  
 
5.1. Analyses. 
 
For all analyses, two-sided tests with significance level 𝛼=0.05 will be used. Where necessary, 
assumptions for parametric testing will be checked prior to analyses. If assumption of normal 
distribution is not met, variable transformation (e.g., log) or nonparametric methods will be used. 
Randomization scheme should insure comparability of the groups on demographic and medical 
characteristics. Baseline characteristics will be compared between the groups using ANOVA for 
numeric values (e.g., age) and chi-square test for categorical variables (e.g., gender). Baseline 
characteristics found to be different between the groups will be used as covariates in the 
primary analyses to control for possible effect of group differences on the outcomes. For the 
primary analysis, PA outcomes will be measured at 2 visits (baseline (BL) and 24 weeks) with 
the exception of accelerometer and 7DPAR data, which will be measured at 3 visits (BL, 24 
weeks, and 48 weeks); cognition and cardiovascular risk factors will also be assessed at 3 
visits. Mixed models analyses will be conducted with a) the inclusion of all available data, 
assuming values missing at random; b) the baseline carry forward (BOCF) imputation method; 
and c) including only the participants who complete the study. For Hypothesis 1.1, changes in 
numeric outcomes measuring PA (e.g., time spent on PA, time spent on sedentary behavior) 
from baseline to week 24 (to week 48 for accelerometer/7DPAR measures) will be compared 
between the iSTEP and control groups using mixed effects models with subject-specific random 
effect. Subject-specific random effects will estimate individual changes in outcomes (slopes) as 
well as individual baseline values (intercept) to take into account natural variability in measured 
values between subjects. The models will regress PA measures on group (iSTEP vs. control), 
time (2 time points), and their interaction. A significant interaction term (p<0.05) would indicate a 
significant treatment effect or, in other words, significant differences in mean changes in 
outcomes over time (slopes) between the two treatment groups. Mixed effects model with terms 
for group, time (3 visits), and their interaction will be used to evaluate effect of iSTEP 
intervention on changes in accelerometer values. In explorative analysis, we will compare daily 

 
12 
 
  
  
 
 
 
 
changes in PA variables measured daily (step count, time spent in PA, and time in SB) between 
iSTEP and control groups using similar method as above, except using many time points (days) 
instead of just 2 or 3. For Hypothesis 1.2, Global Mean T-score will measure cognitive 
performance at all visits; practice effect correction will be applied to values measured at the 24 
and 48 weeks. Again, mixed effects model with subject-specific random effect will be used to 
regress T-score on group (iSTEP vs. control), time (3 time points), and their interaction. We 
hypothesize that a significant interaction term will show that the slope representing an 
improvement in cognition will be the smallest for the control group and the largest for the iSTEP 
group. Similarly, for Hypothesis 2.1, changes in multiple numeric outcomes related to 
cardiovascular disease risk factors (e.g., cholesterol) will be evaluated with separate mixed 
effects models. The models will regress the outcomes on group (control, iSTEP PA/SB, iSTEP 
PA/SB + MedDiet), time (3 time points), and their interaction, including subject specific random 
effect. We hypothesize that a significant interaction will be observed and that it will show greater 
improvements in the outcomes for iSTEP groups, with iSTEP PA + MedDiet group having the 
best results. Similar approach will be used for Hypothesis 2.2, were changes (slopes) in Global 
Mean T-scores will be compared between the iSTEP PA/SB + MedDiet and iSTEP PA/SB 
groups and between the iSTEP PA + MedDiet group and controls. Additional analyses: We will 
conduct exploratory analyses using mixed models to assess changes in diet markers (omega-3, 
DHA, EPA, percent fat intake on the DHQ) over time to assess if there are group differences 
and if these markers predict CVD/NP outcome. Multiple regression analyses will be conducted 
across all participants to examine which factors (PA amount, SB change, MedDiet Score) 
significantly predict NP and CVD risk factors, including metabolic measures and inflammatory 
markers at the 6-month and 12-month visits. We will collect Likert scale data that identify what 
aspect of iSTEP is most useful (e.g., step self-monitoring, step count goals, types of PA/SB 
messages, comparing PA data to other PLWH) and conduct regression analyses to identify 
factors (e.g., PA barriers, SMS adherence) that best predict study outcome and PA/diet  
maintenance.  
     
 
5.2 Power Analysis 
 
For all power 
calculations 
20% dropout 
rate is assumed 
based on prior 
mHealth diet 
interventions119, 
leaving N=40 for 
each of the 
three groups. 
For mixed 
effects models comparing change in outcomes over time between groups, estimates of power 
depend on intra-class correlation (within-subject correlation of outcomes measured at different 
times) and number of total visits, including baseline. For models based on 2 visits (hypothesis 
1.1, except accelerometer), there will be at least 80% power to detect a medium to large effect 
size, Cohen’s d, for the difference in mean change in outcomes from baseline to week 24 visit 
(Fig 1a). For models based on 3 visits (accelerometer /7DPAR values in hypothesis 1.1; 
hypotheses 1.2 through 2.2), there will be at least 80% power to detect a large effect size, d, for 
mean differences in outcome changes over three visits between any of the two groups (Fig 1b).  
0.2
0.4
0.6
0.8
0.7
0.8
0.9
1.0
1.1
1.2
1.3
Intra−class correlation
Effect size (d)
90% Power
80% Power
Figure 1a. Comparing changes in PA 
outcomes between iSTEP group (n = 40 
after 20% dropout) and controls (n = 40 after 
20% dropout) from BL to week 24. Figure 
1b. Comparing changes in accelerometer 
data, cardiovascular disease risk factors, or 
cognitive outcomes between iSTEP 
PA+MedDiet and either of the other two 
groups (n = 40 for each group after 20% 
dropout) from BL to 48 weeks.  

 
13 
 
  
  
 
 
 
 
 
6.0 
PARTICIPANTS 
 
 
6.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document and any subsequent modifications will 
be reviewed and approved by the IRB responsible for oversight of the study. A signed 
consent form will be obtained from the participant (or parent, legal guardian, or person 
with power of attorney for participants who cannot consent for themselves). The consent 
form will describe the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation. A copy of the consent form will be given to the participant, 
parent, or legal guardian, and this fact will be documented in the participant’s record. 
 
6.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the IRB.   
 
6.3 
Study Discontinuation 
 
The study may be discontinued at any time by the IRB as part of their duties to ensure 
that research participants are protected.

 
14