Clinical trial NCT04692467
Conditions: HIV/AIDS Pre Hypertension
Keywords: hypertension HIV
Sponsor: Weill Medical College of Cornell University
Start date: 2021-02-26; Completion date: 2023-12-30
Enrollment: 250 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators are conducting an unblinded pilot randomized control trial of 250 persons living with HIV (PLWH), aged 18-65 years, who receive antiretroviral therapy care at Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), are virally suppressed, and have pre-hypertension (systolic blood pressure (SBP) 120-139 or diastolic blood pressure (DBP) 80-89 mmHg) to be randomized to early hypertension (HTN) treatment versus standard of care (SOC). Participants will be recruited from GHESKIO's HIV clinic. Eligible individuals will complete informed consent and be randomized to early HTN treatment vs. SOC. Participants in early HTN treatment will initiate amlodipine immediately versus those in SOC will initiate amlodipine only if they meet the HTN threshold (SBP ≥140 or DBP ≥90 mmHg) during the study period. All participants will be followed for 12 months.

Detailed description:
The investigators propose a pilot randomized controlled trial to evaluate antihypertensive treatment among people living with HIV (PLWH) with pre-hypertension (pre-HTN) at GHESKIO. This study will provide critical data on the feasibility, benefits and risks of antihypertensive treatment for cardiovascular disease (CVD) prevention among PLWH with pre-HTN that will inform a future definitive trial powered for incident CVD events.

For the pilot study, the investigators will enroll 250 PLWH (18-65 years of age) who have been on antiretroviral therapy (ART) for ≥ 1 years with viral suppression within past 12 months and SBP 120-139 or DBP 80-89 mm Hg and no current antihypertensive treatment; randomize them to "early HTN treatment" or the current standard of care (SOC); and follow them for 12 months. Amlodipine is the recommended first-line anti-hypertensive medication according to Haiti's new primary care HTN guidelines. Participants in the early HTN treatment arm will initiate amlodipine 5 mg immediately, increasing to 10 mg if SBP \>130 mm Hg after 1 month. Participants in the SOC arm will initiate amlodipine only if they develop HTN (SBP ≥140 or DBP ≥90 mm Hg).

Participants that meet study eligibility criteria will proceed to study enrollment visit (\~90 min). Participants will be randomized to early HTN treatment vs. SOC in a 1:1 ratio using a computer-generated random assignment. The research nurse will collect demographic and clinical data, administer a baseline questionnaire, measure unobserved BP, and perform an ECG. The questionnaire includes a CVD medical history, family history, medications, CVD health behaviors (smoking, alcohol, physical activity, and diet) using validated questions that have been used at GHESKIO and are comparable to those used in US cohorts. Enrollment labs (\~15ml of venous blood) including HgbA1c, total cholesterol, high density cholesterol, CD4 (cluster of differentiation 4) cell count, and HIV viral load (unless available from electronic medical record in the past 6 months) will be collected. Samples of serum and plasma will be stored for future studies, with documented consent from participants. The study physician will interpret the ECG and perform an echocardiogram and vascular ultrasound.

Study drug will be dispensed to participants randomized to the early treatment arm with appropriate education and counseling on adherence and potential side effects. Amlodipine will be started at 5mg at enrollment and increased to 10mg if SBP \>130 mm Hg after 1 month for participants in the early treatment arm. Locator and contact information will be verified and follow up appointment given.

After enrollment and randomization assignment (including amlodipine initiation), participants will have follow-up visits either at GHESKIO (months 0.5-1, 3, 6, 9, 12) or in the community / home with community health workers (months 2, 5, 8). All visits will include BP measurement, lifestyle counseling, adherence encouragement, and assessment of adverse events. The GHESKIO visits will also include a physical exam. Participants in the early intervention arm will receive monthly amlodipine refills. Participants in the SOC arm will initiate amlodipine only if they develop hypertension (SBP \>140 or DBP \>90 mm Hg).

At the 12-month study visit, participants will also complete a brief questionnaire about changes in health behaviors and have viral load measured. Participants may return to the HIV clinic at any time for symptoms, questions, or other concerns, and a BP measurement will be taken at each of these encounters. Adverse events will be assessed at each visit. Medical record abstraction will be done by research staff for any hospitalization or death among a participant.

Arms: arm 1: Participants randomized to the early HTN treatment arm will initiate 5mg daily of amlodipine immediately, increasing to 10 mg if SBP \>130 mmHg after 1 month. arm 2: Participants randomized to the SOC arm will not be initiated on any medications initially. They may be initiated on amlodipine only if they develop HTN (SBP ≥140 or DBP ≥90 mm Hg).
Interventions: intervention 1: Amlodipine 5mg
Intervention descriptions: intervention 1: Amlodipine, Haiti's first-line antihypertensive medication, will be administered to the intervention group.

Protocol documents:
Prot_SAP_001.pdf: 
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Treatment of Early Hypertension among Persons Living with HIV in Haiti 
 
NCT number: 
NCT04692467 
 
Sponsored by: 
NIH Fogarty International Center 
 
Principle Investigator WCM: 
Margaret McNairy MD MSc 
 
Principle Investigator GHESKIO: 
Jean William Pape MD 
 
Version Number: 
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Version 1.1 May 22 2020 
 
 
 


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Protocol Summary  
  
Title: Prehypertension in Haiti 
  
Study Summary: We propose an unblinded pilot RCT of 250 persons living with HIV (PLWH), aged 
18-65 years, who receive ART care at GHESKIO, are virally suppressed, and 
have pre-HTN (SBP 120-139 or DBP 80-89 mm Hg) to be randomized to early 
HTN treatment versus standard of care (SOC). Participants will be recruited 
from GHESKIO’s HIV clinic. Eligible individuals will complete informed consent 
and be randomized to early HTN treatment vs. SOC.  Participants in early HTN 
treatment will initiate amlodipine immediately versus those in SOC will initiate 
amlodipine only if they meet the HTN threshold during the study period. All 
participants will be followed for 12 months. The primary outcome is mean 
change in SBP at 12 months between study arms.  Secondary outcomes are 
viral suppression, medication adherence, adverse events, and acceptability. We 
will also assess CVD risk factors and myocardial/vascular dysfunction among all 
participants at enrollment.  
  
Population: We will recruit 250 PLWH from GHESKIO’S HIV Clinic. Inclusion criteria: PLWH 18-65 
years of age, ART duration ≥ 1 year , stable regimen > 6 months, HIV 1-RNA < 
1,000 copies/mL within past 12 months, Pre-HTN (SBP 120-139 or DBP 80-89 
mm Hg), no current antihypertensive treatment, receives HIV care at GHESKIO, 
and willing to provide consent. Exclusion criteria: pregnancy, kidney disease, 
diabetes, advanced illness with limited life expectancy, plans to move out of the 
area within the next year, and clinician determination that patient is unstable on 
ART. 
  
Number of Sites: Single site: GHESKIO Center Port au Prince, Haiti  
  
Study Duration: 2 years 
  
Subject Duration: 12 months 
 
Primary Aim: To assess the feasibility of initiating antihypertensive treatment among PLWH with pre-
HTN through a pilot randomized controlled trial comparing early HTN treatment to SOC. Feasibility 
outcomes include enrollment and retention data, proportion who initiate amlodipine, and incremental 
change in SBP at 12 months between arms. The pilot trial has >80% power to detect differences in 
change in SBP > 4 mm Hg.  
 
 
Secondary Aims: To also examine the following outcomes and measures:  
 
a. Viral suppression compared between study arms at 12 months (defined as HIV-1 RNA < 1000 
copies/ml)  
b. HIV medication adherence compared between study arms at 6 and 12 months (defined as >90% 
adherence using 3-day pill recalls)  
c. Adverse events compared between study arms at 12 months (defined as Grade III-V adverse 
events including hypotension, peripheral edema, and other symptoms which may be related to 
amlodipine) 
d. Acceptability assessed through in-depth interviews with a subset of participants and providers  


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e. CVD risk profile measured among all participants at enrollment including obesity, dyslipidemia, 
diabetes, smoking, physical inactivity, poor diet, and 10-year CVD risk (only among participants > 
40 years) 
f. 
Pre-existing myocardial and vascular dysfunction measured among all participants at enrollment 
using ECG, echocardiography and vascular ultrasound  
  
  
Study endpoints and analysis:  The primary endpoint is the difference in mean change in SBP (mm 
Hg) between study arms at 12 months.  Secondary outcomes include viral 
suppression and medication adherence. We will also measure CVD risk factors 
among participants. We will compare the mean difference in change in SBP 
among participants using a linear mixed-effects model (LMM)accounting for 
repeated measures and correlations within subjects. We will assess incidence of 
HTN using Kaplan Meier methods. Dichotomized outcomes such as HTN will be 
analyzed via generalized linear mixed-effects model (GLMM) at all time pints 
and via Fisher’s exact test and logistic regression at 12 months. Viral 
suppression, medication adherence, and CVD risk factors will be compared 
between study arms using Fisher’s exact test. Longitudinal data such as BMI 
and adherence will be analyzed using LMM and GLMM.  
 
 
 
 
 
 


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1 
KEY ROLES  
 
Principal Investigator (WCM):  
Margaret McNairy, MD, MSc  
Associate Professor of Medicine  
Center for Global Health  
Weill Cornell Medicine  
402 East 67th Street  
New York, NY 10065  
Work: 646-962-8140  
Email: mam9365@med.cornell.edu  
 
Principal Investigator (GHESKIO):  
Jean William Pape, MD  
Professor of Medicine  
Director, GHESKIO Centres  
33 Boulevard Harry Truman  
Port-au-Prince, Haiti   
Work: 509 3702 9366  
Email: jwpape@gheskio.org  
Co-Investigators:   
 
Samuel Pierre, MD 
Senior Research Physician 
GHESKIO Centres  
33 Boulevard Harry Truman  
Port-au-Prince, Haiti   
 
Vanessa Rouzier, MD 
Chief of Pediatrics 
GHESKIO Centres 
33 Boulevard Harry Truma 
Port-au-Prince, Haiti 
 
Myung Hee Lee, PhD  
Assistant Professor, Center for Global Health  
Weill Cornell Medicine  
402 East 67th Street  
New York, NY 10065  
Email: myl2003@med.cornell.edu  
 
Lily Yan, MD, MSc 
Instructor of Medicine 
Center for Global Health  
Weill Cornell Medicine  
402 East 67th Street  
New York, NY 10065  
Email: liy9032@med.cornell.edu  
 
  


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Consultants: 
Suzanne Oparil 
Professor of Medicine 
University of Alabama-Birmingham Medical School 
170 University Blvd 
Birmingham, AL 35233 
 
2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE   
 
2.1  
Background Information 
 
Haiti is located on the western third of the island of Hispaniola in the 
Caribbean Sea and is the poorest country in the Western Hemisphere 
(Figure 1).  Haiti ranks 163 out of 188 countries in the UN Human 
Development Index, which measures economic, education, and health 
factors.1  Haiti has the highest HIV prevalence in the hemisphere (2%); 
currently an estimated 140,000 adults are living with HIV, with two-thirds 
of cases in Port-au-Prince.2-4  Over the last decade, CVD surpassed HIV 
as the leading cause of morbidity and mortality in Haiti.5-8 In 2016, the Global Burden of Disease 
Project estimated the most common cause of death among adults was CVD (27.2% of deaths) in 
comparison to HIV (5.6% of deaths).8 Recent cross-sectional data suggest that 20% of Port-au-Prince 
residents have HTN (29% age-standardized).9 10 Haiti has one of the highest stroke mortality rates in 
the Latin America/Caribbean region, and more than twice that of the neighboring Dominican Republic.11 
One of the strongest stroke risk factors is HTN.  
Cornell-GHESKIO has a 37-year track record of NIH-supported research in Haiti which has informed 
WHO and national policies on prevention and treatment guidelines for HIV and associated 
comorbidities.12-20 GHESKIO was founded in 1982 with research evolving from early epidemiologic 
studies to a major NIH-supported Clinical Trials Unit (CTU) in 2006.  This work contributed to the drop 
in HIV prevalence in the adult population in Haiti, from 6% in 1993 to 2% in 2016, with 60% of those 
infected on ART.12  Since 2012, the CTU has conducted over 20 clinical trials with 98% retention. 
GHESKIO is trusted by the Haitian community, the Haitian Government, and international partners.21  
GHESKIO has never closed its clinics in its tenure, even during the 2010 earthquake, cholera epidemic, 
and periods of political instability. 
Figure 1: Map of Haiti  


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In 2015, GHESKIO established the Non-communicable Disease (NCD) Research Unit, led by the PI of 
this proposal, to evaluate CVD among HIV patients and the general population. With NIH support 
(D42TW0009606-S1), we conducted the first population-based survey of HTN in the slums of Port-au-
Prince and found that 12% of 18-30 year-olds had HTN not accompanied by risk factors such as obesity, 
smoking, and diabetes; this prevalence is ~3 fold higher than similarly aged Black Americans.9 10  In 
2018, we received funding (R01 HL143788 2018-2023; McNairy, PI) to establish the country’s first 
longitudinal cohort to evaluate the epidemiology of HTN including CVD risk factors (e.g. diabetes, 
kidney disease, HIV, diet, inflammation), diseases (stroke, myocardial infarction, heart failure, and 
cardiac death), and poverty-related social determinants. This study dramatically increased our capacity 
to conduct CVD trials through assessment of CVD risk factors, training in ECG and echocardiography, 
validation of community-based BP measurement, and formation of a CVD adjudication committee. In 
2019, the PI of this proposal led a collaboration with the Ministry of Health and international experts to 
develop Haiti’s first national primary care HTN guidelines based on WHO recommended algorithms.22 
23 Amlodipine, was selected for its safety, the lack of laboratory monitoring, and its effectiveness in 
Blacks.24-26 We have also received funding (RESOLVE to SAVE LIVES, PI McNairy) for HTN 
medications and support for guideline implementation.27   
HTN in PLWH is associated with mortality: Cornell-
GHESKIO’s CVD research began with the evaluation of 
CVD outcomes among PLWH who had been followed for 
10 years (the GHESKIO ART Cohort).28 This cohort 
includes 816 HIV-infected adults who started ART in 2005-
2008 when ART first became widely available in Haiti. At 
ART initiation, their median age was 39 years (IQR 33-46), 
58% were female, and their median CD4 count was 281 
cells/mm3 (IQR 250-311). At ART initiation, 5.3% had HTN. 
In 
multivariable 
analysis, 
HTN 
at 
ART 
initiation 
independently predicted mortality during 10 years of follow-up (HR 2.47 [95% CI 1.10-5.57] after 
adjusting for age, sex, and CD4 count at ART start). Figure 2 shows Kaplan Meier survival curves of 
those with normal BP and those with HTN at ART initiation. One-third of the deaths among those with 
HTN were from stroke. Over the median follow-up of 7.3 years, HTN prevalence increased to 43% (HTN 
incidence 34/1000 person-years). HTN prevalence did not differ by gender and was 18% in patients <40 
years, 37% in 40-59 years, and 60% in >60 years. Incident HTN was strongly predictive of death. 
      
Figure 2: Survival of HIV-infected adults 
with and without HTN at ART initiation 


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We analyzed a more recent cohort of 762 PLWH 
who initiated ART between 2013-2015 at 
GHESKIO and found HTN prevalence at time of 
ART initiation doubled to 12% and HTN incidence 
tripled to 108/1000 person-years (Table 1).  Of 
note, 38% of PLWH with pre-HTN at time of ART start developed incident HTN within 18 months.  We 
postulate that the GHESKIO ART Cohort had a higher number of persons with AIDS at ART start as 
compared to this later cohort.  
 
Pre-HTN is associated with increased CVD risk in 
PLWH as compared to adults without HIV: A study from 
the US quantified the increased CVD risk among PLWH 
with pre-HTN as compared to pre-HTN adults without HIV.  
PLWH with pre-HTN had increased risk of myocardial 
infarction (adjusted HR 1.8 [95% CI 1.22-2.68]).29 Our 
preliminary data show that 27% of PLWH with pre-HTN 
compared to 7% of HIV-uninfected adults with pre-HTN 
had elevated 10-year CVD risk, a >3-fold higher 
prevalence (Figure 3). We used the AHA Pooled Cohort Risk Equations to estimate 10-year CVD risk 
among adults 40-79 years.30 Elevated 10-year risk is defined as a predicted risk of >7.5% or having 
diabetes. We included 192 PLWH (median age 45, 72% female, median duration of ART 3 years) and 
153 adults without HIV (median age 41 years, 61% female). The relative contributions of specific risk 
factors explaining this increase among PLWH need further investigation. 
 
2.2  
Scientific Rationale 
HIV-associated CVD has tripled over the past two decades globally and HTN is a major driver of CVD 
among PLWH.29 31-35 Around the globe, >35% of PLWH have HTN, and >50% of PLWH >50 years of 
age have HTN.33 In addition to traditional CVD risk factors, the pathophysiologic mechanisms leading to 
HTN among PLWH may include virologic and treatment-related factors influencing inflammation, 
immune mediation, lipodystrophy and the renin-angiotensin-aldosterone system.36-40  
Figure 3: 
Prevalence of Elevated 10-year CVD risk 
among HIV-infected and uninfected adults  
 
 
 
 
 
Table 1: PLWH who initiated ART 2013-2015 (N=762) 
 
HTN prevalence  
12% 
Pre-HTN prevalence 
22% 
Proportion of pre-HTN PLWH who 
developed HTN in 18 months 
38% 


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The definition of pre-HTN and HTN 
according to WHO, international and 
Haitian Ministry of Health guidelines are 
listed in Table 2.22 23 41  The relationship 
between SBP >115 mm Hg and CVD 
events is linear, with multiple epidemiological studies reporting increased risk of CVD, renal disease, 
and all-cause mortality among adults with pre-HTN.42-46  Untreated pre-HTN is a progressive condition 
of ongoing arteriolar hypertrophy, endothelial dysfunction, and stimulation of the renin-angiotensin 
system which lead to further HTN.47-49  Landmark trials and meta-analyses have shown that 1) treatment 
of pre-HTN in patients with diabetes, chronic kidney disease, and nonobstructive coronary disease 
decreases CVD events and disease progression,50-54 and 2) use of antihypertensive treatment among 
individuals with pre-HTN can prevent progression to HTN.47 These data led to revised guidelines 
recommending antihypertensive treatment at lower BP thresholds among individuals with these 
diseases.22 41 55  In 2017, the US guidelines went further to recommend antihypertensive treatment for 
high-risk adults with SBP >130 or DBP >80 mm Hg, but HIV is not currently included as a high-risk 
category.55  
HIV is associated with equal, if not greater, CVD risk as diabetes;56 yet, the WHO still recommends 
PLWH initiate antihypertensive treatment at the same BP threshold as adults without HIV. Data are 
needed to clarify if initiation of antihypertensive treatment among PLWH with pre-HTN can prevent 
progression to HTN, and ultimately CVD-related mortality. The proposed pilot trial is the first step to 
explore the feasibility, benefits, and risks of initiating antihypertensive treatment among PLWH with pre-
HTN in a well-established HIV program in Haiti, one of the poorest countries in the world.  Knowledge 
gaps include: Is it feasible to initiate and integrate antihypertensive treatment into HIV care among 
relatively healthy PLWH with pre-HTN? Could initiating antihypertensive treatment worsen HIV 
outcomes? What is the BP reduction using amlodipine (which is Haiti’s first-line antihypertensive 
medication) among PLWH with pre-HTN? Data from this pilot trial will inform the design of a future 
multicenter trial powered for incident CVD events. Our goal is to change guidelines to lower the BP 
threshold for initiation of antihypertensive medications among PLWH, should earlier HTN treatment 
prevent CVD.  
 
 
Table 2: Summary of WHO and Haitian HTN definitions and guidelines 
Category 
Definition 
Threshold for initiation of 
antihypertension treatment 
Normal 
SBP < 120 and DBP < 80 
 
Pre-HTN 
SBP 120-139 or  
DBP 80-89 
Diabetes & Chronic Kidney Disease 
(at SBP > 130 or DBP > 90) 
HTN  
SBP > 140 or DBP > 90 
General adults including PLWH 


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3  
POTENTIAL RISKS AND BENEFITS 
 
 
3.1 
Potential Risks 
The risks of this study include loss of confidentiality of study participation, social harms, discomfort, and 
phlebotomy, and adverse events of medications.  GHESKIO has experience conducting research 
studies and has produced teaching materials in Creole for the risks involved in these studies during the 
informed consent process. Further, the occurrence of these adverse events will be closely monitored by 
the study team and reported to the DSMB and IRB. 
A. Loss of Confidentiality:  There is a potential loss of confidentiality of information provided during 
the study including one’s HIV status or diagnosis of hypertension through participation in the 
study.  
 
B. Social Harms:  Participants may experience social harms including loss of privacy, or social 
stigma from perception of being involved in a study related to HIV and cardiovascular disease 
risk factors, such as hypertension. HIV-infected adults are a particularly stigmatized population 
at heightened risk of social harms. 
 
C. Discomfort:  Participants will be asked to complete a questionnaire at study enrollment and at 
the 12 months study visit. The questionnaire includes topics that may be sensitive such as family 
history and health behaviors including smoking, alcohol, physical activity, and diet. 
 
D. Phlebotomy: There is a slight risk of physical discomfort (i.e., slight bruising or tenderness at the 
phlebotomy site) to participants associated with collection of blood sample for hematology, 
chemistry, and HIV viral load.  Approximately 15 mL of venous blood will be collected by 
phlebotomy at study enrollment for these laboratory measures.  Approximately 5 mL of venous 
blood will be collected by phlebotomy for HIV viral load testing at the 12-month study visit.  
 
E. Adverse events:   Amlodipine is recommended by the WHO as first-line medication for elevated 
blood pressure and has a safe side effect profile.22  The most common side effects of amlodipine 
are dizziness and or lightheadedness and peripheral edema. We will monitor adverse events 
using DAIDS criteria for hypotension, peripheral edema and other side effects reported by 
participants that are related to amlodipine.   In other studies, a dose of amlodipine 10mg daily is 
associated with ~ 5-6 mm Hg  reduction in SBP over 1 month.57,58  In one clinical trial 
(CAMELOT), which evaluates the use of amlodipine 10 mg daily among normotensive adults 
with existing cardiovascular disease, 3.3% of participants reported symptoms of lightheadedness 
and dizziness for which amlodipine was discontinued and 5% discontinued amlodipine due to 
peripheral edema.58  We anticipate a similar rate of side effects and adverse events in this study. 
 
Protection against risks:  
The following measures will minimize study risks: 
A. Loss of Confidentiality:  Each participant will be assigned a study identification number consisting 
of a unique code unrelated to any patient identifying information, as per Good Clinical Practice 
guidelines.  Any identifiers linked to the participant will be secured and only available to staff at 


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the GHESKIO Research Center, to ensure subject confidentiality.  Only authorized professionals 
collaborating with the principal investigator will have access to the information. All samples and 
subject data will be coded at the GHESKIO Research Center with the study identification number. 
All source documents will be kept in locked file cabinet. GHESKIO computers and servers are 
protected by firewall protection and are only accessible with a password.  Study staff will be 
trained in Good Clinical Practice regarding maintaining confidentiality. Participants will be asked 
to report any breeches in confidentiality, and these will be reported to the DSMB.  
 
B. Social Harms:  Research staff are trained on how to respond to any social harm reported by a 
participant.  Staff performance will be monitored by the study director, Dr. Pierre during quality 
assurance assessments to ensure minimization of social harms.  Doctors Pape, McNairy, and 
Pierre will be available to assist the study staff in responding to any event that requires further 
management. We routinely educate all patients in the GHESKIO clinic on the importance of 
confidentiality and not sharing information with other patients. Participants will be encouraged to 
report any adverse event or social harms including loss of confidentiality and stigma to study 
staff. These will be documented in source documents and reported to the study team on 
standardized adverse event forms. 
 
C. Discomfort:  As part of the informed consent process, all potential participants will be instructed 
that they do not have to disclose personal information that they are uncomfortable sharing and 
that they can withdraw from the study at any time.   
 
D. Phlebotomy: Participants will be informed of the possible risks of slight bruising or tenderness at 
the site of the blood draw.  They will be encouraged to call or visit the study site if symptoms 
persist or worsen. 
 
E. Adverse events:  Participants will be informed of the possible side effects of amlodipine 
including hypotension and peripheral edema.  We will grade the signs and symptoms of 
hypotension and peripheral edema, or any other reported side effect, using existing DAIDS 
criteria(11) and report Grade III-V events to the DSMB and the GHESKIO and Weill Cornell 
IRB.  Study staff will screen for drug-related adverse events at every study visit.  Participants 
who report adverse events will discuss them with their clinical (non-research) physicians and 
decide together if amlodipine should be discontinued.  All clinical care of any adverse event will 
be provided free of charge by GHESKIO.  
 
  
3.2  
Known Potential Benefits  
The proposed study has the potential to change the paradigm of antihypertensive treatment in PLWH, 
both in the US and abroad. If the study finds earlier initiation of antihypertensive treatment is a form of 
CVD prevention, then we can reduce CVD events and related mortality in PLWH.  
 
Participants in the proposed study will also benefit from having free screening for hypertension and 
free medications. Moreover, participants who are diagnosed with a cardiovascular risk factor, 
abnormal laboratory value (e.g. elevated hemoglobin A1C), and/or other diseases will be referred to 
ongoing clinical care at GHESKIO or a GHESKIO-affiliated hospital.  GHESKIO is affiliated with 4 
hospitals in Port-au-Prince including Hospital Bernard Mevs, Hospital du Canape, Hospital Saint-
Damien, and Hospital Saint Francois de Sales.  Receipt of clinical care is not dependent on study 


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participation.  The GHESKIO NCD Research Unit follows national guidelines for the management of 
chronic diseases including hypertension, diabetes, kidney disease, among others.  All WHO Essential 
Medications are available at the clinic including aspirin, amlodipine, hydrochlorothiazide, hydralazine, 
bisoprolol, enalapril, digoxin, metformin, insulin, among others.  The GHESKIO affiliated hospitals 
provide free care to patients who cannot pay.    
 
If the intervention study arm, early HTN treatment, is found to be effective in the primary study 
outcome of reduced mean SBP  > 4 mm Hg between study arms, we will continue amlodipine in 
participants randomized to the intervention arm and offer amlodipine to all participants in the standard 
of care study arm.   
 
 
 


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4 
STUDY PROTOCOL 
4.1  
Study Objective 
We propose a pilot randomized controlled trial to evaluate antihypertensive treatment among PLWH 
with pre-HTN at GHESKIO. This study will provide critical data on the feasibility, benefits and risks of 
antihypertensive treatment for CVD prevention among PLWH with pre-HTN that will inform a future 
definitive trial powered for incident CVD events. For the pilot study, we will enroll 250 PLWH (18-65 
years of age) who have been on ART for ≥ 1 years with viral suppression within past 12 months and 
SBP 120-139 or DBP 80-89 mm Hg and no current antihypertensive treatment; randomize them to 
“early HTN treatment” or the current standard of care (SOC); and follow them for 12 months. 
Amlodipine is the recommended first-line anti-hypertensive medication according to Haiti’s new 
primary care HTN guidelines. Participants in the early HTN treatment arm will initiate amlodipine 5 mg 
immediately, increasing to 10 mg if SBP >130 mm Hg after 1 month. Participants in the SOC arm will 
initiate amlodipine only if they develop HTN (SBP >140 or DBP >90 mm Hg). We hypothesize that 
early HTN treatment will not impact viral suppression and be feasible and safe, with a reduction in BP 
at 12 months compared to SOC. The primary aim is to assess the feasibility of initiating 
antihypertensive treatment among PLWH with pre-HTN through a pilot randomized controlled trial 
comparing early HTN treatment to SOC. Feasibility outcomes include enrollment and retention data, 
proportion who initiate amlodipine, and incremental change in SBP at 12 months between arms. The 
secondary aim includes analyzing the following measures: viral suppression, HIV medication 
adherence, adverse events, acceptability, CVD risk profile, and pre-existing myocardial and vascular 
dysfunction. 
 
4.2  
Study Site 
The trial will be conducted at the GHEKSIO Centers in Port au Prince, Haiti.  
 
4.3  
Study Population 
The study population will include 250 PLWH from 
GHESKIO’s HIV clinic. Inclusion and exclusion 
criteria are in Table 3.  We included younger 
PLWH given the early onset of HTN in Haiti and 
limited the upper age to 65 years given the low 
incidence of HIV above this age. We exclude 
PLWH with kidney disease (<60mL/min/1.73m2 
using 
CKD-Epi 
equation) 
because 
Haiti’s 
guidelines recommend furosemide as first-line 
treatment for this group. We exclude diabetics (defined as fasting glucose >126 mg/dL or non-fasting 
glucose >200 mg/dL, or taking diabetes medications)(140, 141) because Haiti’s guidelines recommend 
initiation of antihypertensive medications when SBP > 130 mmHg or DBP > 80 mmHg. Individuals on a 
protease inhibitor with ritonavir will be excluded as ritonavir can increase levels of amlodipine. Women 
who become pregnant will be censored at time of pregnancy. 
Table 3. Inclusion and exclusion criteria for the trial 
Inclusion criteria 
Exclusion criteria 
• PLWH 18-65 year of age 
• ART duration ≥ 1 year, stable 
regimen > 6 months 
• HIV 1-RNA < 1,000 copies/mL 
within past 12 months 
• Pre-HTN (SBP 120-139 or DBP 
80-89 mm Hg) 
• No current antihypertensive 
treatment 
• Receives HIV care at GHESKIO 
• Willing to provide consent 
• Pregnancy  
• Kidney disease or 
diabetes 
• Protease 
inhibitor/ritonavir 
• Advanced illness with 
limited life expectancy 
• Plans to move out of 
the area within the 
next year 
• Clinician determination 
that patient is unstable 
on ART 
 


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4.4  
Recruitment and Informed Consent 
Screening and recruitment will follow GHESKIO Clinical Trials Unit procedures that have been highly 
successful in NIH trials.  We will identify and invite potential participants both 1) in-person at GHESKIO’s 
HIV clinics using real time BP measurements and 2) from GHESKIO’s electronic medical record (EMR) 
using BP measurements in the past 12 months, age, ART duration, viral suppression, and no current 
antihypertensive treatment.  PLWH meeting these eligibility criteria will be tagged in the EMR as 
participants for recruitment and a list will be given to the study team.   
The research nurse will approach patients in the HIV clinics, or call PLWH on the list to introduce the 
study and invite interested individuals for informed consent and then a screening visit. After confirming 
basic eligibility criteria, the research nurse will initiate informed consent procedures among eligible 
participants. The informed consent process consists of two education sessions, followed by assessment 
of understanding and written informed consent.  
After informed consent, participants will be assigned a unique study ID number and undergo a screening 
visit with review of eligibility criteria and screening labs. Pre-HTN is defined as >2 BP measurements of 
SBP 120-139 mm Hg or DBP 80-89 mm Hg on separate days.  All BP measurements will be done 
according to AHA/WHO guidelines.22 55 Screening labs will be collected (urine or serum pregnancy test, 
fasting or random glucose, and creatinine) to evaluate if the patient is pregnant, has diabetes, or kidney 
disease. We will document the number screened and reasons for study exclusion.   
In 2018, 18,872 PLWH on ART received care at GHESKIO with mean duration of ART of 5.6 years, 76% 
on first-line regimens, 86% virally suppressed, and median age of 35 years. We estimate 3,819 PLWH 
at GHESKIO satisfy the eligibility criteria. Based on our past enrollment experience, we are confident 
250 participants can be enrolled from this sampling frame in 6 months. 
 
4.5  
Study Enrollment 
Participants that meet study eligibility criteria will proceed to study enrollment visit (~90 min). Participants 
will be randomized to early HTN treatment vs. SOC in a 1:1 ratio using a computer-generated random 
assignment. The research nurse will collect demographic and clinical data, administer a baseline 
questionnaire, measure unobserved BP, and perform an ECG.  The questionnaire includes a CVD 
medical history, family history, medications, CVD health behaviors (smoking, alcohol, physical activity, 
and diet) using validated questions that have been used at GHESKIO and are comparable to those used 
in US cohorts. Enrollment labs (~15ml of venous blood) including HgbA1c, total cholesterol, HDL, CD4 
and HIV viral load (unless available from EMR in the past 6 months) will be collected. Samples of serum 
and plasma will be stored for future studies, with documented consent from participants.  The study 
physician will interpret the ECG and perform an echocardiogram and vascular ultrasound. 
Study drug will be dispensed to participants randomized to the early treatment arm with appropriate 
education and counseling on adherence and potential side effects. Amlodipine will be started at 5mg at 


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enrollment and increased to 10mg if SBP >130 mm Hg after 1 month for participants in the early 
treatment arm. Locator and contact information will be verified and follow up appointment given.  
 
4.6 
Follow-up study visits and retention efforts 
After enrollment and randomization assignment (including amlodipine initiation), participants will have 
follow-up visits either at GHESKIO (months 0.5-1, 3, 6, 9, 12) or in the community / home with CHWs 
(months 2, 5, 8) (table 4). All visits will include BP measurement, lifestyle counseling, adherence 
encouragement, and assessment of adverse events. The GHESKIO visits will also include a physical 
exam. Participants in the early intervention arm will receive monthly amlodipine refills. Participants in 
the SOC arm will initiate amlodipine only if they develop hypertension (SBP >140 or DBP >90 mm Hg). 
At the 12-month study visit, participants will also complete a brief questionnaire about changes in health 
behaviors and have viral load measured.  Participants may return to the HIV clinic at any time for 
symptoms, questions, or other concerns, and a BP measurement will be taken at each of these 
encounters.  Adverse events will be assessed at each visit. Medical record abstraction will be done by 
research staff for any hospitalization or death among a participant.  
To encourage retention and minimize missing data, GHESKIO staff will call participants 1-2 days prior 
to each study visit and will also call and track participants who miss a scheduled study visit.  Since 2012, 
GHESKIO has recruited HIV-infected adults for 16 HIV trials with 98% retention.   
 
4.7  
Study Measures and Schedule 
Description of study measures and their schedules are listed in table 4.  
Table 4: Study Measures and Schedule 
Required forms: 
 
SCREEN 
ENROLL 
M1 
M2 
M3 
M5 
M6 
M8 
M9 
M12 
Screening Eligibility Form: inclusion criteria, 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Screening Labs: urine/serum pregnancy test, fasting 
or random glucose, Creatinine 
X 
 
 
 
 
 
 
 
 
 
Individual Characteristics 
 
 
 
 
 
 
 
 
 
 
Locator information: address and cell phone, 
friend/family member’s cell phone 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sociodemographics: age, sex 
 
X 
 
 
 
 
 
 
 
 
Socioeconomic factors: income, education, 
occupation, marital status, children.  
 
X 
 
 
 
 
 
 
 
 
Medical History: history of CVD risk factors, CVD, 
HIV, tuberculosis 
 
X 
 
 
 
 
 
 
 
 
Family History: stroke or MI in parents and 4 oldest 
siblings 
 
X 
 
 
 
 
 
 
 
 
Health behaviors: current cigarette smoking,90 
alcohol160-163, physical activity 164   
 
X 
 
 
 
 
 
 
 
X 
Multidimensional Poverty: child death, educational 
attainment, household construction materials, 
possessions 
 
X 
 
 
 
 
 
 
 
 
Clinical Measures 
 
 
 
 
 
 
 
 
 
 
Physiologic: height, weight 
 
X 
 
 
 
 
 
 
 
 


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Blood pressure in community 
 
X 
 
X 
 
X 
 
X 
 
 
Blood pressure at clinic 
 
X 
X 
 
X 
 
X 
 
X 
X 
ECG 
 
X 
 
 
 
 
 
 
 
 
Echocardiography and vascular ultrasound 
 
X 
 
 
 
 
 
 
 
 
Enrollment Labs: HgbA1c, total cholesterol, HDL, 
CD4, VL 
 
X 
 
 
 
 
 
 
 
 
12M Labs: VL 
 
 
 
 
 
 
 
 
 
X 
Medical record abstraction: diagnoses codes (ICD-
9), laboratory measures, diagnostic imaging, and 
cause of death among participants who receive 
clinical care from the GHESKIO NCD clinic, a 
GHESKIO-affiliated hospital, or other health facility 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Management 
 
 
 
 
 
 
 
 
 
 
Medication Adherence 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical record abstraction for development of HTN 
after enrollment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Medical record abstraction for clinical management 
of CVD risk factors: smoking, HLD, DM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intervention related 
 
 
 
 
 
 
 
 
 
 
Amlodipine initiation form 
 
X 
 
 
 
 
 
 
 
 
In depth interviews about feasibility, acceptability 
 
 
 
 
 
 
 
 
 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
BP measurement: All BP measurements will follow AHA/WHO guidelines using semi-automated 
electronic cuffs (OMRON 742-5 series at home and HEM907 in clinic) of 3 BPs separated by >1 
minute with the individual seated at rest.22 55 The average of the 3 BPs is the BP for the visit. 
HIV services for all participants:  Provision of HIV services, including ART, adhere to national 
guidelines.65 66 The first-line ART regimen is TDF/3TC/dolutegravir; second-line regimens include 
protease inhibitors. Patients who are virally suppressed are seen in the GHESKIO HIV clinic every 6 
months for adherence assessment and medication refills.  HIV-1 RNA viral load is measured annually. 
BP is measured at every clinic visit.   
Early HTN treatment vs. SOC procedures: The only difference between study arms is the BP threshold 
at which amlodipine is initiated.  Participants in the early HTN treatment arm will initiate amlodipine 5 
mg immediately followed by an increase to 10 mg if SBP >130 mm Hg after 1 month or more.  
Participants in the SOC arm will initiate the same algorithm but at the standard BP threshold for HTN 
which is SBP >140 or DBP >90 mm Hg in two measurements on different days. There are no known 
drug-drug interactions between the first-line ART and amlodipine. Haiti’s guidelines recommend 
amlodipine as the first line regimen for diabetic individuals as well.  
Clinical management of CVD risk factors and diseases:  Any participant diagnosed with a risk factor or 
disease through study procedures will be escorted to the GHESKIO clinic or affiliated hospital in Port-
au-Prince for clinical care and further evaluation by clinicians who are independent of the research 
team (see Human Subjects).  Clinical care is provided free of charge. 
 


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Study Outcomes:  The primary quantitative outcome is the difference in mean change in SBP (mm 
Hg) between study arms at 12 months.  Secondary outcomes include viral suppression defined per 
WHO guidelines of HIV-1 RNA <1,000 copies/ml and amlodipine and ART medication adherence 
defined as >90% adherence using 3-day pill recalls, as recommended by the ACTG at enrollment, 3, 
6, 9 and 12 months.67 We will assess for serious adverse events including DAIDS Grade III-V 
symptoms of hypotension, peripheral edema and other symptoms related to medications at every 
study visit (see Human Subjects).68  Feasibility and acceptability will be assessed by enrollment and 
retention statistics as well as qualitative in-depth interviews among a subset of 30 participants in the 
early HTN treatment arm and all study providers at 12 
months. We will assess participant attitudes towards the 
study drug amlodipine. Interviews will explore attitudes about 
initiating amlodipine, positive/negative effects, satisfaction, 
intent to continue, home BP measurement, and perceived 
CVD risk.  We will interview providers about implementation 
challenges and unintended consequences.  Interviews will be 
~45 minutes, conducted in Creole, audio-recorded, 
transcribed verbatim, and translated into English for analysis 
using Atlas-ti. Among all participants, we will measure CVD 
risk factors at enrollment (Table 5). In participants >40 years, we will calculate their 10-year AHA 
atherosclerotic CVD (ASCVD) risk at enrollment.69  Pre-existing myocardial and vascular 
dysfunction will be measured at enrollment using ECG, echocardiogram, and vascular ultrasound 
(Sonosite M-Turbo ultra-sound with P21-x probe). Dysfunction is defined as evidence of left ventricular 
hypertrophy, diastolic and/or systolic dysfunction, ischemia, increased carotid intima media thickness 
(surrogate for atherosclerosis), and carotid-femoral pulse wave velocity (measure of arterial stiffness) 
using imaging criteria from the American and European Societies of Echocardiography and Minnesota 
criteria.70-73 Dr. Pierre is trained and certified in echocardiography and has experience measuring 
these parameters with quality assurance from Cornell cardiology in the NHLBI R01 HL143788.   
 
4.8  
Research staff training and data management 
Research staff will be trained in Good Clinical Practice and will receive training for study procedures and 
a training on AHA/WHO BP measurement guidelines including certification prior to study enrollment and 
recertification every 6 months. Participants will be identified by an unique study ID number and no 
participant identifying information will be recorded. Data on research forms will be entered by a data 
clerk and supervised by Adias Marcelin (Data Manager) into NIH-approved REDCap data management 
system, which is encrypted, and password protected. Dr. McNairy and Dr. Pierre will oversee data quality 
control and assurance using CTU procedures. They will review consent documents and REDCap data 
files for internal validity and completeness.  Dr. McNairy will travel monthly to Haiti to meet with the study 
team and will participate in weekly conference calls with Dr. Pierre. 
 
4.9  
Analysis plan and statistical power considerations 
Table 5: CVD risk factors 
Factors included in ASCVD:  gender, age, 
race (white or other), total cholesterol (mg/dL), 
HDL cholesterol (mg/dL), SBP, received 
treatment for HTN, diabetes (HbA1c >7 or on 
medications), smoking 
Other CVD factors: BMI (kg/m2), waist 
circumference, poor diet (WHO STEPS), 
physical inactivity (WHO STEPS), CD4 count, 
viral load 


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Sample size and power: With a sample of 250 participants and 6 time points for BP measurements for 
each participant, we have 80% power with alpha 0.05 to detect a difference in change in SBP of 4 mm 
Hg or more between the study arms at 12 months (assuming consistent difference across time and a 
conservative correlation among measurement of 0.95).74 We will present summary statistics (e.g., 
mean and SD of pre, post, and difference within and between arms) in publication for readers and 
future meta-analyses. 
 
Aim 1: Feasibility will be measured as the proportion of eligible participants willing to participate in the 
trial and their retention, and the proportion initiating amlodipine. We will compare the mean difference 
in change in SBP among participants from enrollment to 12 months in each study arm using linear 
mixed-effects model (LMM) accounting for repeated measures and correlations within subjects, where 
the time*treatment interaction will serve as “primary” parameter addressing differential slopes for the 
two arms. We anticipate the two arms will have similar baseline characteristics due to randomization, 
and therefore the primary analysis will not adjust for baseline variables.  If baseline variables are 
imbalanced, we will adjust factors in regression and report as sensitivity analysis. We will assess 
incidence of HTN using Kaplan Meier methods.  We will analyze dichotomized outcomes (SBP <120 
and DBP <80) at all time points via generalized mixed-effects model and at 12 months via Fisher exact 
tests and logistic regression. In other sensitivity analyses, we will explore the following issues: 1) 
compliance/adherence (e.g., per protocol analysis); 2) missing data/dropout (via last-value-carried-
forward, multiple imputation or inverse-probability weighting); 3) competing risks (e.g., death); 4) joint 
modeling (of longitudinal and survival data); and 5) changepoint (of treatment initiation in SOC arm).   
 
Aim 2:  The proportion of participants in each study arm with viral suppression (HIV-1 RNA < 1000 
copies/mL) at 12 months will be compared between study arms using the Fisher exact test; we 
assume participants who are lost to follow-up or dead at 12 months will have HIV-1 RNA > 1000 
copies/mL. Other categorical data including medication adherence, CVD risk factors (e.g. diabetes) 
will be analyzed similarly. Longitudinal data such as BMI and adherence (continuous or 
binary/categorical) will be analyzed accounting for repeated measures within participants, via LMM 
and GLMM as described above. We will also consider Generalized estimating equation-based method 
(so called, marginal or population-averaged model) and will report consistency or meaningful 
discrepancy.  Acceptability will be assessed in qualitative interviews by Dr. Pierre who is trained in 
qualitative research using interview information transcribed verbatim, translated into English, and then 
coded for analysis using a thematic coding scheme.  We will also describe adverse events among all 
participants.  
 
4.10  Timeline 
This study will be conducted over two years (8 quarters). In Q1, we will finalize study operating 
procedures, data collection tools, and staff training. Screening, recruitment, and enrollment will be 
conducted in Q2-3. Participants will be followed for 12 months from Q2 to Q7. In-depth interviews will 
be conducted at 12-month clinic visits during Q6-7. In Q7-8, we will finalize data analysis and 
dissemination. 


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4.11  Potential challenges and solutions 
Insufficient number of eligible individuals to meet target: We will monitor enrollment weekly and expand 
recruitment to other GHESKIO-affiliated clinics if needed. Missing data and migration: GHESKIO’s CTU 
has a history of >98% retention in clinical trials. We will conduct the 12-month questionnaire by phone 
among those who cannot return. Since the treatment initiation threshold varies across study arms, 
blinding is not feasible. We will explore the use of placebo and blinding for the future trial.     
 
4.12  Summary and future directions 
 
There is an urgent need for CVD prevention among PLWH with elevated BP who have alarmingly high 
risk of CVD events and related mortality.  This study is the first step towards evaluating the safety and 
benefits of earlier HTN treatment among PLWH and will inform a larger trial powered for CVD events. 
If we demonstrate feasibility and find benefit, the larger trial to follow may shift the paradigm of 
antihypertensive treatment for CVD prevention in PLWH, both in the US and abroad.  
 
4.13 Data Safety and Monitoring Board and Procedures: 
 
The following monitoring steps will be taken to monitor and ensure the safety of research volunteers:  
 
• 
The study and consent forms must be approved by Institutional Review Boards in Haiti and 
Weill Cornell prior to the start of the trial.  
• 
The Principle Investigator will receive a weekly log of adverse events and will review this log 
each week with the local study team and international collaborators. 
• 
The study team is responsible for reporting all severe Grade III-V adverse events or death 
suffered by study participants to the IRBs and DSMB within 24 hours of knowing of the event. 
• 
The Principle Investigator must renew IRB approval every year through submission of an 
annual update including a description of all adverse events. 
 
A Data Safety Monitoring Board (DSMB) will ensure the safety of trial participants through monitoring 
study procedures, implementation, study findings and review of all adverse events including social 
harms 
 
The DSMB will meet before enrollment starts to review the study protocol for protection of human 
participants. The DSMB will then meet every six months.  Prior to their meeting, they will receive 
summary reports of study progress, all adverse events including loss of confidentiality, stigma, social 
harms and Grade III-V adverse events reported by a study participant.  Any severe adverse event, 
Grade III or IV or death will be reported to the DSMB Chair, within 24 hours of documentation by study 
staff, who will also report it to Dr. McNairy (PI) and Dr. Pape (Haitian Site PI).  After each meeting, the 
DSMB will provide a written report on the status of the study and their recommendations for any 
modifications of the study. This report will be provided to the PI and IRBs. The DSMB had the right to 
halt the study for safety concerns at any time. 
 


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