Table 4 Clinical trials with macrophage-based cardiovascular disease therapeutics
From: Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets
Study | Agent | Drug target | Patient cohort | Enrollment | Primary end point | Main outcomes | Phase | NCT number | Citation |
|---|---|---|---|---|---|---|---|---|---|
Inhibition of macrophage recruitment | |||||||||
Colombo et al. (2016) | Bindarit | A CCL2 inhibitor | Patients submitted to coronary stenting and using a bare metal stent | 148 | In-segment late loss | Bindarit helped patients prevent restenosis. | Phase 2 | NCT01269242 | |
Gilbert et al. (2011) | MLN1202 | Monoclonal antibody against CCR2 | Patients with risk factors for cardiovascular disease | 108 | The change in median CRP level from baseline to day 57 | Patients had significantly lower levels of CRP than the placebo. | Phase 2 | NCT00715169 | |
Inhibition of foam cell formation and macrophage survival | |||||||||
NA | MEDI6570 | Antibody against LOX1 receptor | Patients with previous MI | 423 | Non-calcified plaque volume measured by CTA | NA | Phase 2 | NCT04610892 | NA |
Nissen et al. (2006) | Pactimibe | ACAT inhibitors | Patients with coronary disease | 534 | NA | Treatment with ACAT inhibitors did not improve percent atheroma volume. | Phase 2 | NCT00185042 | |
Meuwese et al. (2009) | Pactimibe | ACAT inhibitors | Patients with familial hypercholesterolemia | 796 | The maximum CIMT | Pactimibe had no effect on atherosclerosis but was associated with an increased incidence of major cardiovascular events compared with the placebo. | Phase 2&3 | NCT00151788 | |
Pradhan et al. (2022) | Pemafibrate | A selective PPARα modulator | Patients with diabetes | 10,544 | A composite of nonfatal MI, ischemic stroke, coronary revascularization, or death from cardiovascular causes | The incidence of cardiovascular events was not lower among those who received pemafibrate than the placebo. | Phase 3 | NCT03071692 | |
Puato et al. (2010) | Atorvastatin | A macrophage accumulation inhibitor | Patients with hypercholesterolemic | 60 | NA | Macrophage accumulation was significantly reduced in the plaques of patients treated with statins. | NA | NCT01053065 | |
Elkhawad et al. (2012) | Losmapimod | A p38 MAPK inhibitor | Patients with atherosclerosis on stable statin therapy | 99 | Change from baseline in average TBR across all segments in the index vessel | High-dose losmapimod reduced vascular inflammation in the most inflamed regions, concurrent with a reduction in inflammatory biomarkers and FDG uptake in visceral fat. | Phase 2 | NCT00633022 | |
O’Donoghue et al. (2016) | Losmapimod | A p38 MAPK inhibitor | Patients with AMI | 3503 | The composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12 | The use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. | Phase 3 | NCT02145468 | |
Newby et al. (2014) | Losmapimod | A p38 MAPK inhibitor | Patients with NSTEMI | 526 | Inflammation (hsCRP concentration at 12 weeks) and infarct size (AUC for troponin I over 72 h or hospital discharge, whichever was earlier) | The p38 MAPK inhibition with losmapimod was well tolerated in NSTEMI patients and might improve outcomes after ACS. | Phase 2 | NCT00910962 | |
Fox et al. (2014) | Ivabradine | A regulatory molecule of PI3K/Akt/mTOR | Patients with stable coronary artery disease | 19,102 | A composite of death from cardiovascular causes or nonfatal MI | The addition of ivabradine did not improve outcomes. | Phase 3 | NCT02446990 | |
Rodriguez et al. (2012) | Rapamycin | A mTOR inhibitor | Patients with bare metal stent implantation | 200 | Compare overall costs (in-hospital and follow-up costs of the two revascularization strategies (OR and DES) at 1, 3 and 5 years follow-up | There were no differences in effectiveness between the two revascularization strategies. | Phase 4 | NCT00552669 | |
Stähli et al. (2022) | Everolimus | A mTOR inhibitor | Patients with STEMI undergoing PCI | 150 | The change in MI size | The inhibition of mTOR with everolimus did not reduce MI size or MVO at 30 days. | Phase 1&2 | NCT01529554 | |
Jamialahmadi et al. (2022) | Trehalose | A macrophage autophagy activator | Patients with history of MI and evidence of systemic inflammation | 15 | The change in arterial wall inflammation, assessed by quantifying 18F-FDG uptake in carotid arteries and ascending aorta. | No significant reduction in arterial wall inflammation could be observed. | Phase 2 | NCT03700424 | |
Regulation of macrophage function | |||||||||
Tardif et al. (2019) | Colchicine | Broad immunosuppression | Patients with MI within 30 days before enrollment | 4745 | A composite of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization | Colchicine decreased the risk of the composite endpoint compared with placebo. | Phase 3 | NCT02551094 | |
Nidorf et al. (2020) | Colchicine | Broad immunosuppression | Patients with chronic coronary artery disease | 5522 | A composite of cardiovascular death, spontaneous MI, ischemic stroke, or ischemia-driven coronary revascularization | Colchicine decreased the risk of the composite endpoint compared with placebo. | Phase 3 | ACTRN12614000093684 | |
NA | Colchicine | Broad immunosuppression | Patients with ACS | 500 | NA | NA | Phase 4 | NCT01906749 | NA |
NA | Colchicine | Broad immunosuppression | Patients with ACS | 80 | NA | NA | Phase 2&3 | NCT00754819 | NA |
NA | Colchicine | Broad immunosuppression | Patients with CAD undergoing PCI | 132 | NA | NA | Phase 4 | NCT05130892 | NA |
NA | Colchicine | Broad immunosuppression | Patients with MI | 7063 | MACE | NA | Phase 3 | NCT03048825 | NA |
NA | Colchicine | Broad immunosuppression | Patients with ischemic stroke or at high risk of transient ischemic attack | 3154 | Recurrence of non-fatal ischemic stroke or non-fatal MACE, or vascular-related death | NA | Phase 3 | NCT02898610 | NA |
NA | Hydroxychloroquine | Broad immunosuppression | Patients with MI | 125 | Rate of cardiovascular adverse events (MI, death, hospitalization for unstable angina and heart failure) | NA | Phase 4 | NCT02648464 | NA |
NA | Hydroxychloroquine | Broad immunosuppression | Patients with CAD and hsCRP >1 mg/l | 35 | Change in fasting hsCRP level | NA | Phase 4 | NCT02874287 | NA |
Ridker et al. (2019) | Methotrexate | Broad immunosuppression | Patients with atherosclerosis | 4786 | a composite of nonfatal MI, nonfatal stroke, or cardiovascular death | Low-dose methotrexate did not reduce levels of IL-1β, IL-6, or CRP and did not result in fewer cardiovascular events than placebo. | Phase 3 | NCT01594333 | |
NA | Methotrexate | Broad immunosuppression | Patients with multivessel CAD and hsCRP >2 mg/l | 40 | Reduction in plaque volume, measured by CTA | NA | Phase 2&3 | NCT04616872 | NA |
Razavi et al. (2018) | Dexamethasone | Broad anti-inflammatory effect | Patients with symptomatic PAD receiving PTA or atherectomy | 285 | 12-month primary patency was defined as a composite of freedom from binary restenosis and clinically driven target lesion revascularization | After 12 months of follow-up, the patient’s restenosis decreased. | Phase 4 | NCT01983449 | |
Ridker et al. (2017) | Canakinumab | Inhibition of the IL-1β pathway | Patients with previous MI and elevated plasma CRP levels | 10,066 | Nonfatal MI, nonfatal stroke, or cardiovascular death. | The inhibition of the IL-1β pathway with canakinumab led to a significantly lower rate of recurrent cardiovascular events compared with placebo. | Phase 3 | NCT01327846 | |
Abbate et al. (2020) | Anakinra | IL-1 receptor antagonist | Patients with STEMI | 99 | The AUC for hsCRP, measured at baseline, 72 h, and day 14 | The IL-1 blockade with anakinra significantly reduced the systemic inflammatory response compared with placebo. | Phase 2&3 | NCT01950299 | |
Kron et al. (2021) | Anakinra | IL-1 receptor antagonist | Patients with cardiac sarcoidosis | 28 | Limited to 28 days and additional assessments are for safety purposes only | Patients had significantly lower cardiac and systemic inflammation compared with placebo. | Phase 2 | NCT04017936 | |
Sayed et al. (2016) | Xilonix | Monoclonal antibody specifically targeting IL-1α | Patients undergoing percutaneous SFA revascularization | 43 | Clinically significant target vessel restenosis, time to restenosis, and incidence of MACE | At 12 months of follow-up, there was no difference between Xilonix and placebo. | Phase 2 | NCT01270945 | |
Ridker et al. (2021) | Ziltivekimab | Monoclonal antibody against IL-6 | Patients with chronic kidney disease and hsCRP >2 mg/l | 264 | hsCRP measured 12 weeks after treatment initiation | Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. | Phase 2 | NCT03926117 | |
NA | Ziltivekimab | Monoclonal antibody against IL-6 | Patients with chronic kidney disease and CRP ≥ 2 mg/l | 6200 | Time to first MACE | NA | Phase 3 | NCT05021835 | NA |
Broch et al. (2021) | Tocilizumab | Monoclonal antibody against IL-6 receptor | Patients within 6 h of STEMI and undergoing PCI | 200 | The myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days. | Tocilizumab increased myocardial salvage in patients with acute STEMI. | Phase 2 | NCT03004703 | |
Kleveland et al. (2016) | Tocilizumab | Monoclonal antibody against IL-6 receptor | Patients with NSTEMI | 120 | The between-group difference in the AUC for hsCRP during hospitalization (days 1–3) | Tocilizumab reduced hsCRP levels compared with the placebo. | Phase 2 | NCT01491074 | |
Meyer et al. (2021) | Tocilizumab | Monoclonal antibody against IL-6 receptor | Patients with out-of-hospital cardiac arrest | 80 | The reduction in CRP response from baseline until 72 h in patients treated with tocilizumab evaluated by mixed-model analysis for a treatment-by-time interaction | Treatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in patients. | Phase 2 | NCT03863015 | |
NA | Sarilumab | Monoclonal antibody against IL-6 receptor | Patients with active rheumatoid arthritis | 20 | Changes in carotid atheroma plaque assessed by ultrasonography | NA | Phase 4 | NCT04350216 | NA |
NA | Etanercept | A TNF-α inhibitor | Patient with STEMI | 200 | NA | NA | Phase 4 | NCT01372930 | NA |
