Highlights
-
•
EPIC-HIV is a clinical trial of the PCSK9 inhibitor alirocumab among adults with HIV.
-
•
The primary outcome is arterial inflammation assessed using 18 F-FDG PET/CT.
-
•
Assesses coronary plaque, endothelial function, lipids, and inflammatory/immune markers.
-
•
One hundred eighteen participants have been randomized.
-
•
Primary results are expected in 2026.
ABSTRACT
Rationale
People with HIV (PWH) are at increased risk of cardiovascular disease. Moderate lipid lowering with statins has been demonstrated to reduce cardiovascular risk among PWH. Accordingly, evaluation of more potent lipid-lowering strategies for prevention is needed, especially for PWH at higher risk. Prior research suggests that proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors safely lower low-density lipoprotein cholesterol by 60% among people with HIV, but the impact of PCSK9 inhibitors on arterial inflammation, endothelial function, coronary plaque, or markers of immune dysfunction among PWH remains unknown.
Methods
The effect of PCSK9 inhibition on cardiovascular risk in treated HIV infection study is a randomized, placebo-controlled, and double-blinded clinical trial. Adults at least 40 years old with treated and virally suppressed HIV and at least one cardiovascular risk factor (primary prevention) or a prior cardiovascular event (secondary prevention) are randomized in a 2:1 ratio to alirocumab or a matching placebo injected subcutaneously. 18 F-fluorodeoxyglucose positron emission tomography/computed tomography, coronary computed tomographic angiography, and flow-mediated dilation of the brachial artery are conducted at baseline and after 1 year of treatment. The primary study outcome is the change in arterial inflammation assessed using the target-to-background ratio of the most diseased arterial segment on positron emission tomography/computed tomography from baseline to 1 year, and key secondary endpoints will include the change in noncalcified coronary plaque on coronary computed tomographic angiography, change in endothelial function, and safety according to the intention-to-treat principle.
Enrollment
One hundred eighteen participants were randomized. The mean age was 59.5 years, and 6% were female.
Conclusions
The effect of PCSK9 inhibition on cardiovascular risk in treated HIV infection study will provide evidence regarding the mechanisms by which potent lipid lowering with PCSK9 inhibitors may alter the pathogenesis of atherosclerosis among PWH.
Trial registration
Graphical abstract
People with HIV (PWH) are at increased risk of atherosclerotic cardiovascular disease (ASCVD) compared to people without HIV. , Dyslipidemia, lipodystrophy, and pro-atherogenic lipid abnormalities may result from older antiretroviral therapy regimens, especially those containing protease inhibitors ,,,, as well as HIV infection itself. Lowering low-density lipoprotein cholesterol (LDL-C) with statins (hydroxymethylglutaryl coenzyme A reductase inhibitors) prevents cardiovascular events in the general population. The randomized trial to prevent vascular events in HIV (REPRIEVE) demonstrated that pitavastatin reduces risk of cardiovascular events by 35% compared to placebo among PWH at low-to-moderate ASCVD risk. Recent guidelines have expanded the proportion of PWH who are recommended statins by lowering the predicted 10-year ASCVD risk thresholds. ,
Further evidence regarding ASCVD prevention strategies for those at higher risk, including those already on statins, is needed. While safe and effective, statins do not eliminate risk. Within REPRIEVE, 39% (89/225) of the first major adverse cardiovascular events occurred among individuals randomized to pitavastatin. Some residual risk among PWH is likely inflammatory risk, but some may be due to residual cholesterol risk. In the REPRIEVE mechanistic substudy, pitavastatin lowered inflammatory lipids, but not other non-lipid inflammatory markers, , and many of the pathways not modified with statin therapy associated with cardiovascular events were immune/inflammatory pathways. In the general population with ASCVD, additional lowering of LDL-C using additional agents on top of statin therapy reduces cardiovascular events and cardiovascular mortality. , Residual cholesterol risk may be addressable with high-intensity statin therapy, adding additional lipid-lowering therapies, or more potent and targeted lipid lowering.
An important contributor to ASCVD is arterial inflammation, which may be driven by inflammatory cholesterol particles and by immune dysregulation. Arterial inflammation can be assessed noninvasively using 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG/PET CT). PWH have increased arterial inflammation compared to people without HIV. , Among PWH, arterial inflammation is correlated with low-attenuation (“vulnerable”) coronary plaque independent of traditional ASVCD risk factors. Arterial inflammation is correlated with circulating markers of inflammation and immune activation, including high-sensitivity C-reactive protein, interleukin-6, and activated monocytes (CD14dimCD16+; nonclassical).
There are mixed findings regarding the impact of LDL-lowering on arterial inflammation especially among PWH. In the general population, statins are associated with reduced arterial inflammation, ,,, suggesting that inflammatory lipid particles may drive arterial inflammation. Similarly, lipoprotein apheresis lowers LDL-C and arterial inflammation, suggesting that these effects are not purely a result of the pleotropic anti-inflammatory properties of statins. Among PWH, Boczar et al studied rosuvastatin 10 mg for 6 months and demonstrated a reduction in arterial inflammation with statin therapy ( n = 17) compared to placebo ( n = 16). In contrast, Lo et al did not find a difference in arterial inflammation with atorvastatin 20 to 40 mg daily compared to placebo among 21 participants with adequate 18 F-FDG/PET CT imaging. If inflammatory cholesterol particles promote arterial inflammation among PWH, then inflammatory and cholesterol risk may be intertwined among PWH.
The impact of lipid-lowering using statin therapy on noncalcified coronary plaque (an important predictor of future major adverse cardiovascular events among PWH ) assessed using coronary computed tomography angiography (CCTA) has been evaluated in several studies in PWH. A study of 40 individuals by Lo et al demonstrated that 1 year of atorvastatin was associated with reduced noncalcified plaque volume. The REPRIEVE mechanistic substudy, which included measurement of biomarkers and CCTA (but not arterial inflammation), demonstrated that 2 years of treatment with a moderate intensity statin was associated with a modest reduction in noncalcified plaque volume and greater decreases in inflammatory cholesterol particles.
Endothelial dysfunction is common among PWH and likely contributes to cardiovascular risk among PWH. ,, One randomized clinical trial previously demonstrated that pravastatin 40 mg daily for 8 weeks improved endothelial function compared to placebo among PWH as assessed using flow-mediated dilation of the brachial artery. In contrast, low-dose methotrexate had no impact on endothelial function among PWH.
Besides statins, one established therapeutic target for pharmacologic cholesterol-lowering is proprotein convertase subtilisin kexin 9 (PCSK9). PCSK9 is the enzyme responsible for degradation of the LDL receptor. Circulating PCSK9 may be higher among PWH, especially those co-infected with hepatitis C virus. Higher PCSK9 levels are associated with higher levels of circulating interleukin 6 (IL-6), a potent predictor of cardiovascular events and mortality among PWH. Furthermore, higher serum PCSK9 levels are associated with coronary endothelial dysfunction among PWH independent of LDL-C, strengthening the rationale for studying PCSK9 inhibitors among PWH and including endothelial function as an endpoint.
Monoclonal antibodies against PCSK9 are approved by the Food and Drug Administration and have been demonstrated to safely and dramatically lower LDL-C, ,,,,,, regress coronary atherosclerotic plaque, and prevent cardiovascular events. , The ODYSSEY and FOURIER trials demonstrated that treatment with alirocumab and evolocumab, respectively, on top of maximally tolerated high-potency statin, was associated with lower risk of major adverse cardiovascular events compared to placebo in a secondary prevention population, with local injection-site reactions as the only safety signal. , Recently, the VESALIUS-CV trial demonstrated that evolocumab was associated with a 19% to 25% lower risk of major adverse cardiovascular events among patients with atherosclerosis or diabetes without a prior myocardial infarction (“primary prevention population”), with 68% treated with high-intensity statins at baseline. Currently available PCSK9 inhibitors are administered subcutaneously, which may be particularly attractive to PWH with high pill burden or who have switched to long-acting injectable antiretroviral therapy, and help address low uptake of statins and high statin discontinuation rates. ,, The impact of PCSK9 inhibitors on high sensitivity C-reactive protein is negligible in the general population, and their impact on arterial inflammation has not been investigated.
Two completed studies and one study that was terminated early have investigated PCSK9 inhibitors among PWH. Among PWH, a randomized clinical trial called EvolocumaB Effect on LDL-C Lowering in SubJEcts with Human Immunodeficiency VirRus and INcreased Cardiovascular RisK (BEIJERINCK) demonstrated that PCSK9 inhibition with evolocumab 420 mg subcutaneously monthly for 24 weeks lowered LDL by 57% on top of maximally tolerated statin therapy without major safety concerns. While providing strong evidence that PCSK9 inhibition can safely lower LDL-C among PWH, that study did not include imaging assessments of arterial inflammation or coronary plaque. A small pilot study with 20 participants demonstrated that PCSK9 inhibition with evolocumab for 6 weeks is associated with improved coronary endothelial function among PWH compared to placebo. Our group previously initiated a clinical trial of the PCSK9 inhibitor bococizumab, but the trial was stopped after Pfizer discontinued their bococizumab program. Within that study, 11 participants (5 on statin) were randomized: 5 patients received bococizumab and 6 placebo. There were no safety issues, and no significant changes in HIV RNA level, CD4, or CD8+ T cells over 8 weeks (compared to placebo, unpublished data). We observed a significantly larger LDL reduction in the bococizumab arm relative to placebo (−58% vs −13%, P =.028). Reductions in other parameters were numerically larger for the bococizumab arm vs placebo: LpPLA 2 (−41% vs +2%, P =.096), Lp(a) (−64% vs +41%, P =.34), hsCRP (−18% vs +28% P =.65), and oxidized LDL (−26% vs +6% P =.36). The two completed studies of PCSK9 inhibitors in HIV did not include measures of arterial inflammation or coronary plaque.
To determine the mechanisms by which PCSK9 inhibition might prevent ASCVD events among PWH, we designed the effect of PCSK9 inhibition on cardiovascular risk in treated HIV infection (EPIC-HIV) study as a randomized clinical trial. Eligible participants are individuals aged 40 years and older with treated HIV infection and known ASCVD or at least one cardiovascular risk factor. The intervention is alirocumab (Sar236553/REG 727), a fully humanized monoclonal antibody against PCSK9 developed by Regeneron Pharmaceuticals/Sanofi, at a dose of 150 mg subcutaneous injection every 2 weeks for 52 weeks. The comparator is matching a placebo, with participants randomized 2:1 to active drug and placebo, respectively. The key endpoints include 18 F-FDG PET/CT imaging to assess arterial inflammation; coronary computed tomographic angiography to assess coronary plaque; flow-mediated dilation of the brachial artery to assess endothelial function; and measurements of circulating lipid levels, inflammatory markers, and immune activation.
Methods
Study approval and registration
The study was submitted to the Food and Drug Administration as an Investigational New Drug Application (IND 135964) and determined to be exempt from the IND regulations. The study and consents were approved by the University of California San Francisco Institutional Review Board. The study is registered on clinicaltrials.gov: https://clinicaltrials.gov/study/NCT03207945 .
Major study objectives
The primary objective is to determine whether PCSK9 inhibition using alirocumab improves arterial inflammation as assessed by 18 F-FDG-PET/CT in PWH who are treated and virally suppressed and with known ASCVD or at risk for ASCVD. Statins and LDL apheresis have improved these endpoints in the general population but the impact of more intensive LDL lowering with PCSK9 inhibitors on HIV-associated vascular inflammation is not known. We will correlate changes in lipid parameters, markers of inflammation, and immune activation (including oxidized LDL, Lp(a), Lp-PLA2, sCD14, and T cell activation) with changes in arterial inflammation.
Secondary objectives include assessing the impact of PCSK9 inhibition on markers of inflammation, coronary atherosclerosis assessed using CCTA, especially noncalcified plaque volume and pericoronary adipose tissue attenuation and on endothelial function assessed with flow mediated vasodilation of the brachial artery.
Study design
EPIC HIV is a prospective, randomized, placebo-controlled, double-blinded clinical trial. Details of the planned study conduct are included in the Study Protocol ( Figure 1 ).
Study Diagram. Study diagram of EPIC-HIV study.
Inclusion and exclusion criteria
Study population: Adults with HIV infection who are on stable antiretroviral therapy with a prior cardiovascular event (secondary prevention) or at elevated risk for cardiovascular disease (primary prevention) and have evidence of arterial inflammation are eligible.
Inclusion criteria: (1) HIV infection on continuous ART with a HIV RNA <200 copies/mL for ≥12 weeks prior to study entry, (2) age ≥ 40 years, (3) documented cardiovascular disease (including prior myocardial infarction or ischemic stroke) or at least one cardiovascular risk factor (diabetes mellitus, current smoking, hypertension, dyslipidemia, hsCRP ≥ 2 mg/L, family history of cardiovascular disease) with a mean arterial target-to-background ratio (TBR) assessed with 18 F-FDG-PET/CT of >1.6 (to enrich the study sample for those likely to benefit from the intervention by excluding the few PWH without any arterial inflammation; details below in Primary Endpoint ), (4) fasting LDL-C ≥ 70 mg/dl; fasting TG ≤ 600 mg/dl; (5) individuals who meet ACC/AHA criteria for statin therapy must be on a stable dose of statin for at least 4 weeks unless they are statin intolerant, refuse to take a statin, or have a contraindication to statin use.
This baseline arterial TBR cutoff excludes the rare individual with HIV who lacks appreciable arterial inflammation. Although 5% to 10% of individuals without HIV have lower TBRs, it is rare that PWH will fall below this range. In fact, all participants in our prior PCSK9 study with bococizumab, as well as our canakinumab trial (with similar inclusion criteria to this trial), had baseline arterial TBR above this threshold. Individuals with treated hepatitis B or C, on stable doses of lipid-lowering therapy, diabetes medication (not including insulin), and/or anti-hypertensive medication will be allowed in the study.
Exclusion criteria: (1) pregnancy or breastfeeding, (2) uncontrolled hypertension or diabetes requiring insulin, (3) recent cardiovascular or cerebrovascular event or procedure during the past 90 days, (4) history of hemorrhagic stroke or lacunar infarct, (5) female who has either not used a least 1 highly effective method of birth control for 1 month prior to screening or is not willing to use such a method during treatment and for 105 days after end of treatment, (6) cancer within the last 5 years (except for cutaneous basal cell or squamous cell cancer), (7) nephrotic syndrome or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2. Additional inclusion/exclusion criteria are outlined in Appendix I- Clinical Trial Protocol.
Randomization and Blinding
Randomization: Eligible individuals who provide written informed consent are randomized in a 2:1 ratio (alirocumab: placebo) by an experienced investigational pharmacy using a computer-generated randomization scheme generated by an individual outside of the study. The 2:1 ratio balances improved precision in mechanistic imaging and biomarker endpoints from increased allocation to the investigational agent while requiring only approximately 12.5% larger total sample to maintain the same power. Research staff directly involved in study conduct remain blinded to study allocation. Cholesterol panels are reviewed by an independent monitor at an external site who is not working with study participants; all study investigators, clinical research coordinators, and study participants are blinded to cholesterol panels obtained during the study.
Intervention and Comparator
The intervention is Alirocumab (Sar236553/REG 727), a fully humanized monoclonal antibody against PCSK9 developed by Regeneron Pharmaceuticals/Sanofi, at a dose of 150 mg subcutaneous injection every 2 weeks for 50 weeks (25 injections). The comparator is matching placebo in an identical injection. The investigational product may be administered in the abdominal wall, thigh, or upper arm. The first dose is administered in a clinically observed setting, and subsequent injections every 2 weeks can be self-administered at home or injected by study staff. Individuals who prefer to be self-injected are trained to use the auto-injector. If injections are performed by study staff concurrent with a planned study visit, they occur after all blood collection and measurements have been conducted. Doses are administered every 14 days from day 1 to 351 (window −1/+4 days). If a dose is missed within 7 days, the dose may be given at that time and then resume the original dosing schedule, but if the missed dose is not recognized within 7 days, then the dose is skipped and the next dose is given according to the original schedule. Participants are instructed to keep the investigational product refrigerated until use at 2 to 8 °C and are provided with an insulated container for transportation. All participants who chose to do self-injection are instructed to record their injections and dates in a diary, and these are collected by the research team.
Primary Endpoint
The primary endpoint is change in arterial inflammation from baseline to week 52 measured using 18 F-FDG PET/CT. 18 F-FDG PET/CT is a noninvasive tool to assess arterial inflammation in vivo that has been used in prior studies comparing people with and without HIV ,, and as an endpoint for clinical trials of interventions among PWH. ,,, 18 F-FDG PET/CT is performed according to a standard, well-validated research protocol with high reproducibility as previously described , and consistent with our prior studies. ,,, Macrophages primarily use glucose for energy so metabolically active inflammatory atherosclerotic plaques have higher 18 F-FDG uptake compared to areas without plaque or areas with stable calcified plaque.
For image acquisition, participants are instructed to eat a low-carbohydrate dinner the day prior to the scan and fast for at least 10 hours. Five minutes prior to intravenous injection of 18 F-FDG, the capillary blood glucose is measured and required to be less than 150 mg/dl. Then 10 miCi of 18 F-FDG is administered intravenously. Participants recline supine in a quiet, temperature-controlled room with a warm blanket where they can watch television but not read, converse, or do any physical activity. Two hours (120 minutes) after 18 F-FDG administration, images are acquired on either a Discovery (GE Healthcare) or Biograph Vision (Siemens) scanner. Images are acquired with a 3 mm slice thickness with attenuation correction.
Images are transmitted to the imaging core lab (Massachusetts General Hospital). All measurements are performed by core lab staff blinded to randomization assignment and clinical variables. The arterial activity is assessed on the ascending aorta and right and left carotid arteries. For each vessel, the mean standardized uptake value (SUV mean ) is measured. Background is defined as the mean standardized uptake value of the superior vena cava (for aortic activity) or jugular veins (for carotid activity). TBRs are obtained by dividing mean target activity by the corresponding blood background activity. The index vessel is defined as the vessel with the highest mean TBR at baseline. Additionally, the most diseased segment is defined as the 1.5 cm segment (within the index vessel) that has the highest TBR at baseline and evaluable at both time points. The primary endpoint is the mean of the maximum TBR of 3 contiguous slices of the most diseased segment ( Figure 2 ).
Measurement of FDG PET/CT Endpoints. Original from Tawakol et al (2013) (reproduced along with figure legend with permission). Regions of interest are drawn around the artery (in axial orientation) to provide a maximum standardized uptake values (SUV) for each region of interest (ROI). This is repeated along the length of the vessel (every ∼3 mm along the long axis of the vessel) to provide a stack of ROI that compose the whole vessel. Then, the background corrected maximum SUVs are averaged to provide a whole vessel target-to-background ratio (TBR). Similarly, the most diseased segment (MDS) TBR is produced by identifying the ROI with the single highest SUV, then constructing as stack of 3 ROI using that “most diseased” ROI, combined with its immediate inferior and superior neighbors. PET/CT, positron emission tomography/computed tomography.
Secondary Endpoints
A key secondary endpoint is changed in noncalcified coronary plaque (NCP) volume from baseline to week 52 assessed using CCTA. Noncalcified coronary plaque volume is thought to be the biologically modifiable portion of coronary plaque. It has been used as an endpoint in several clinical trials of cardiovascular therapies for PWH, including the REPRIEVE mechanistic substudy of the impact of pitavastatin on coronary plaque in PWH. ,, As in PREPRIEVE, we employ a standardized CCTA protocol including an electrocardiogram-synchronized noncontrast coronary artery calcium scoring scan and contrast-enhanced coronary CT angiography. Images are acquired with a 256-slice GE Revolution CT scanner according to Society of Cardiac Computed Tomography guidelines at baseline and week 52. Metoprolol and nitroglycerin may be administered prior to the study to optimize heart rate and coronary vasodilation. Images are transmitted to the core laboratory (Massachusetts General Hospital) which also served as the CT core lab for REPRIEVE. Plaque measurements are made on a dedicated workstation using QAngio CT (Medis Medical Imaging) blinded to randomization group and clinical variables. Coronary borders are defined by the software and then manually edited. Plaque is defined as voxels between the inner and outer coronary artery walls; composition including calcified and noncalcified plaque volume are defined based on the attenuation of the plaque voxels. Low attenuation plaque is defined as the subset of noncalcified plaque volume <30 Hounsfield Units.
The impact of PCSK9 inhibition on endothelial function is assessed in a subset of study participants using flow-mediated dilation (FMD) of the brachial artery according to our standard research protocol at baseline (performed twice and averaged), week 24, and week 52. ,,, HIV is associated with impaired endothelial function, with more advanced immune dysfunction associated with worse endothelial function. Endothelial function improves with initiation of antiretroviral therapy. , Participants are instructed to fast and avoid caffeine and nicotine for 12 hours prior to measurement. Brachial artery diameter and hyperemic velocity are measured with a Vivid7 with a 10 MHz linear array probe (GE). Brachial artery diameter is measured after 10 minutes of rest as the average of the end-diastolic diameter from 5 cardiac cycles assessed by M-mode. Flow-mediated dilation, an endothelial-dependent process, is assessed by inflating a blood pressure cuff to suprasystolic pressures to induce forearm ischemia and the measuring the brachial artery diameter at 15 second intervals between 30- and 120-seconds following cuff dilation. The impact of PCSK9 inhibition on endothelial function is assessed in a subset of study participants using flow-mediated dilation (FMD) of the brachial artery diameter. The primary outcome for FMD is the absolute change from baseline to 52 weeks in percent of flow-mediated dilation. Secondary outcomes include change from baseline to week 24 and week 24 to week 52, change in microvascular function assessed as maximal reactive hyperemia (RH) defined as the Doppler mean velocity time integral of the first three beats after cuff release and change in endothelial-independent FMD assessed 10 minutes after administration of sublingual nitroglycerin (0.4 mg). Images are transferred to a dedicated workstation and interpreted using dedicated software (Medical Imaging Applications). The technician performing and interpreting the images is blinded to treatment assignment and clinical variables.
Change in hematopoietic activity including bone marrow, spleen, and lymph node metabolic activity are also assessed using 18 F-FDG PET/CT as change in SUV and TBR values from baseline to week 52.
In addition to clinical labs for safety monitoring at screening, entry, week 4, week 12, week 24, week 36, week 48, week 52, and week 60, blood will be collected at the same time points (except screening) for banking of plasma and serum, which will be processed according to standard protocols and stored at −80 °C. Peripheral blood mononuclear cells will be collected at entry, week 24, and week 52, processed according to standard protocols, and cryopreserved in liquid nitrogen storage. Most biomarkers, including measurement of lipid parameters (LDL-C, TC, Apo-B, non-HDL-C, HDL-C, triglycerides, Lp(a), Oxidized LDL, Lp-PLA 2 ), HIV disease (viral load, CD4 count), inflammatory markers (D-Dimer, CRP, IL-6, MCP-1, IL-18, sCD14, TF, and sCD163), and immune activation (T-cell and monocyte activation), will be assessed at baseline, week 24, and week 52.
Measurements of immune activation, including T-cell and monocyte activation, will be conducted at the National Institutes of Health Division of Infectious Diseases using multiparameter spectral cytometry. All laboratory personnel will be blinded to the randomization group and clinical variables.
Safety Endpoints
The most common anticipated safety event based on clinical trials of PCSK9 inhibitors in the general population is local injection-site reactions.
Because of uncertainty regarding the safety of extremely low LDL-C levels, an external study coordinator at a different site will monitor LDL-C levels in real time. Individuals with two consecutive LDL-C measures <10 mg/dl are reported to the Safety Monitoring Committee. Similarly, investigators are notified if there is a fasting triglyceride level >800 mg/dl.
Laboratory tests for safety are conducted at times defined in the Schedule of Events via the clinical laboratory, including hematology, chemistry, liver function, creatinine kinase, HIV viral load, and cluster of differentiation 4 (CD4) count.
All adverse events are recorded in a case report form from the time of receipt of the first study dose until the final study visit. Severity and causality are assessed by the investigator. Serious adverse events and adverse events of special interest result in notification to Regeneron Pharmaceuticals/Sanofi, the Human Research Protection Program, and the Data Safety Monitoring Committee.
Data Safety Monitoring
A safety monitoring committee was convened, including an expert in HIV medicine, a lipid expert, and an infectious disease expert. The committee periodically meets based on enrollment milestones to review safety data and provide recommendations to the study team.
Statistical Plan
Statistical methods are described in detail in the Statistical Analysis Plan.
Power and Sample Size Considerations
The original sample size was planned to be 140 participants assuming a 10% dropout and 8% exclusion for poor-quality images resulting in 132 individuals with analyzable FDG PET/CT. This sample size would allow for at least 80% power to detect a difference in mean TBR of 0.102, which is <5% of the anticipated mean baseline TBR between alirocumab versus placebo using a two-sided t test at the 5% significance level. This is based on an estimated standard deviation of change in TBR of 0.18 and a mean baseline TBR of 2.23. Based on prior studies of statins, which have achieved 8% to 19% reductions in TBR over shorter time periods, the <5% detectable with this sample is less than the minimal clinically significant difference based on prior studies of statins. Of note, most prior studies of interventions using 18 F FDG PET/CT as a primary outcome have had much smaller sample sizes than our originally planned sample size (see Table I ), including all of those which specifically included PWH.
Table I
Clinical trials with 18 F FDG PET/CT assessment of arterial inflammation.
| Study | Population | Intervention/ comparator | Sample size and numbers evaluated | Primary finding |
|---|---|---|---|---|
| Fayad Lancet 2011 | ASCVD | Dalcetrapib/placebo for 6 months | 130 randomized, 106 with complete image sets (54 and 52) | No change in MDS TBR ( P =.51) |
| Elkhawad JACC Cardiovasc Imaging 2012 | ASCVD on statins | Losmapimod (once or twice daily)/placebo for 84 days | 99 randomized, 93 with complete image sets (32, 32, 29) | −0.10 for change in mean TBR of “active” segments for each active group compared to placebo ( P =.013 for high dose and P =.019 for low dose) |
| Tawakol JACC 2013 | ASCVD with baseline arterial inflammation | Atorvastatin 10 mg/atorvastatin 80 mg for 12 weeks | 83 randomized, 67 with complete image sets | −10.6% in index MDS TBR for 80 mg vs 10 mg ( P =.01) |
| Nitta JACC Cardiovascular Imaging 2013 | Type 2 diabetes | Pioglitazone/glimeperide | 50 randomized, 47 with complete image sets (25 and 22) | −0.21 in left main trunk with pioglitazone ( P =.032) |
| van Wijk JACC 2014 | Familial hyperlipidemia | Lipoprotein apheresis, 1 session | 12 | −11.8% in index MDS TBR ( P =.037) |
| Lo Lancet HIV 2015 | PWH with subclinical ASCVD | Atorvastatin 20 or 40 mg/placebo for 12 months | 40 randomized, 21 with complete image sets (10 and 11) | No significant difference in MDS TBR ( P =.77) |
| Gaztanaga Atherosclerosis 2015 | Recent acute coronary syndrome | VIA-2291/ placebo for 24 weeks | 52 randomized, 45 with complete image sets (24 and 21) | No change in mean of max TBR of index vessel ( P =.34) |
| Emami Atherosclerosis 2015 | ASCVD on statin with arterial inflammation | BMS-582949/atorvastatin 80 mg/ placebo | 72 randomized 1:1:1, 53 with complete image sets | No change in whole vessel TBR |
| Hsue JACC 2018 | PWH | Canakinumab 150 mg once | 10 | −10% in mean TBR ( P =.046) |
| Ripa Circ Cardiovasc Imaging 2021 | Type 2 diabetes | Liraglutide 1.8 mg daily/placebo to 24 weeks | 102 randomized, 99 with complete image sets (50 and 49) | No difference in mean change of active segment TBR ( P =.53) |
| Boczar J Nucl Cardiol 2022 | PWH | Rosuvastatin 10 mg daily/usual care for 6 months | 35 (17 and 18) | −15% difference in TBRmax between groups ( P =.035) |
| Jamialahmadi Biomed Pharmacother 2022 | Prior MI and elevated hsCRP | Trehalose 15 g intravenously weekly/placebo | 15 (2:1 intervention: control) | No difference in MDS TBR |
| Solomon Annals Rheumatic Diseases 2023 | Rheumatoid Arthritis nonresponders to methotrexate | Tumor necrosis factor (TNF) inhibitor (TNFi)/sulfasalazine and hydroxychloroquine | 159 randomized, 115 with complete image sets (58 and 57) | No change in MDS TBR between groups (0.79) |
| Srinivasa Clin Inf Dis | PWH | Eplerenone 50 mg BID/placebo for 12 months | 26 (13 and 13) | −26% difference in MDS TBR between groups ( P =.007) |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
