Table 1.
Summary of selected phase 2 and 3 clinical trials published in 2022
| Study (NCT), [Reference] | Trial design | Drug, doses | Primary endpoint | Results |
|---|---|---|---|---|
| Anticoagulants | ||||
| AXIOMATIC-SSP | Phase 2, R, DB, PC, dose-rangingN = 2366 patients with mild-to-moderate acute non-lacunar stroke or TIA with evidence of arterial atherosclerosis on background treatment with open-label aspirin (100 mg) and clopidogrel (75 mg) for 21 days, followed by OL aspirin thereafterFU: 90 days | Milvexian 25 mg QD, 25, 50, 1000, or 200 mg BID or matching placebo | Primary efficacy endpoint: composite of ischaemic stroke during treatment or incident infarct on brain MRI at 90 days. Main safety endpoint: major bleeding, defined as BARC type 3 or 5 bleeding | There was no apparent dose response. Milvexian numerically reduced the risk of clinical ischaemic stroke (excluding covert brain infarction) in the intention-to-treat population at all doses except 200 mg BID; at 25–100 mg BID, milvexian produced an ∼30% relative risk reduction vs. placebo. The rate of major bleeding was similar for milvexian and placebo. |
| PACIFIC-AF (NCT04218266) | Phase 2, R, DB, PC, dose-findingN = 862 with AFFU = 12 weeks | Asundexian 20 or 50 mg QD vs. apixaban, 5 mg QD | Composite of major or clinically relevant non-major bleeding according to ISTHs criteria, assessed in all patients who took at least one dose of study medication | Asundexian at 20 mg and 50 mg daily had lower observed rates of bleeding compared with apixaban. The rate of AEs was similar in the three groups. |
| PACIFIC-AMI Investigators (NCT04304534) | Phase 2, R, DB, PC, PG, dose findingN = 1601, within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. 99% underwent PCI before randomizationFU: 368 days | Asundexian 10, 20, or 50 mg or placebo QD | Prespecified main safety outcome: bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. Prespecified efficacy outcome: composite of CV death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo. | Asundexian, added to aspirin plus a P2Y12 inhibitor, resulted in dose dependent, near-complete inhibition of FXIa activity (>90% inhibition at 50 mg) without a significant increase in bleeding and a low rate of ischaemic events. The main safety outcome was similar with asundexian or placebo (HR 0.98; 0.71–1.35). The efficacy outcome was similar with asundexian (10, 20, or 50 mg) or placebo, respectively, (pooled asundexian 20 and 50 mg vs. placebo: HR 1.05; 0.69–1.61). |
| PACIFIC-Stroke (NCT04304508) | Phase 2b, DB, PC, R, dose-finding trialN = 1808 with acute (within 48 h) non-cardioembolic ischaemic stroke FU: 26–52 weeks |
Asundexian 10, 20, or 50 mg/day or placebo | Efficacy outcome: effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation.Safety outcome: major or clinically relevant non-major bleeding | Asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo. |
| Cardiac amyloidosis | ||||
| HELIOS-A (NCT03759379) | Phase 3, R, PA, OLN = 164 adult patients with hATTR amyloidosis with polyneuropathy (vutrisiran, n = 122; patisiran reference group, n = 42; external placebo, n = 77)FU = 16 months | Vutrisiran 25 mg s.c. Q3M) vs. patisiran 0.3 mg/kg IV Q3W vs. an external placebo group (APOLLO study) | Change from baseline in the modified Neuropathy Impairment Score + 7 at 9 months compared with the placebo group of the APOLLO phase 3 study (external placebo group) at month 9 | Vutrisiran significantly improved multiple disease-relevant outcomes vs. external placebo, with an acceptable safety profile.The 9-month endpoints will be analysed at 18 months with the addition of other secondary endpoints. |
| Diuretics | ||||
| ADVOR study (NCT03505788) | Phase 4, R, DB, PAN = 519Acute decompensated HF on ≥40 mg of furosemide, signs of volume overload and BNP >250 pg/mL | Acetazolamide (500 mg OD) or placebo added to standardized i.v. loop diuretics (at a dose equivalent to twice the oral maintenance dose). The intervention continued for 3 days or until the time of decongestion | Successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy | The addition of acetazolamide to loop diuretic therapy resulted in a greater incidence of successful decongestion (42.2% vs. 30.5%; P < 0.001). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis. The incidence of worsening kidney function, hypokalaemia, hypotension, and adverse events was similar in the two groups. |
| Glucose-lowering drugs | ||||
| SURMOUNT-1 (NCT04184622) | Phase 3, DB, R, PCN = 2539 with a BMI of ≥30, or ≥27 and at least one weight-related complication, excluding diabetesFU = 72 weeks | Tirzepatide 5 mg, 10 mg, or 15 mg once weekly or placebo | Percentage change in weight from baseline and a weight reduction of ≥5% | Tirzepatide provided substantial and sustained reductions in BW vs. placebo (–15.0%, –19.5%, and –20.9% vs. –3.1%, respectively). 50% and 57% of participants in the 10-mg and 15-mg groups had a reduction in body weight ≥20% (3% with placebo; all P < 0.001). |
| SURPASS-3 MRI (NCT0388297) | Phase 3, R, OL, PGN = 502 with T2DM, BMI ≥25 kg/m2, stable weight, insulin-naive, on treatment with metformin alone or in combination with a SGLT2I for at least 3 months before screeningFU: 52 weeks | Tirzepatide: 5, 10, or 15 mg s.c. once weekly or s.c. injection once per day of titrated insulin deglude | Change from baseline in liver fat content (LFC measured by MRI-PDFF) at week 52 using pooled data from the tirzepatide 10 and 15 mg groups vs. insulin degludec. | The absolute reduction in LFC at week 52 was significantly greater for the pooled tirzepatide 10 and 15 mg groups (–8.09%, SE 0.57) vs. the insulin degludec group (–3.38%, 0.83). The reduction in LFC was significantly correlated (P ≤ 0.0006) with baseline LFC, reductions in VAT, ASAT, and body weight in the tirzepatide groups. |
| SURPASS-5 (NCT04039503) | Phase 3, R, DB, PAN = 475 with T2DM inadequately controlled on insulin glargine with or without metforminFU = 40 weeks | Tirzepatide: 2.5, 5, 10, or 15 mg once weekly or volume-matched placebo | Mean change from baseline in HbA1c at week 40 | Higher percentages of patients treated with tirzepatide vs. those treated with placebo had HbA1c <7% (85–90% vs. 34%; P < 0.001 for all). |
| SURPASS J-mono (NCT03861052) | Phase 3, DB, RN = 615 adults with T2DM who discontinued oral antihyperglycaemic monotherapy or were treatment-naïveFU = 52 weeks | Tirzepatide 5 mg, 10 mg, or 15 mg once weekly or dulaglutide (0.75 mg once per week) | Mean change in HbA1c from baseline at week 52 measured in the modified intention-to-treat population | Tirzepatide was superior compared with dulaglutide for glycaemic control and reduction in bodyweight. |
| Hypertrophic cardiomyopathy | ||||
| VALOR-HCM (NCT04349072) | Phase 3, R, DB, PCN = 112 with symptomatic oHCM (NYHA class III–IV or NYHA class II with exertional syncope or near syncope) who meet guideline criteria for septal reduction therapy (SRT) | 16-week placebo-controlled period, a 16-week treatment with mavacamten; and a 96-week long-term extension period where all patients will continue to receive mavacamten | Composite of the number of patients who decide to proceed with SRT prior to or at week 16 and the number of patients who remain SRT-guideline eligible (LVOT gradient of ≥50 mmHg and NYHA class III–IV or class II with syncope) at week 16 in the mavacamten group compared with the placebo group | In oHCM patients with intractable symptoms, after 32 weeks of treatment with mavacamten showed sustained reduction in the proportion proceeding to SRT or remaining guideline eligible, with similar effects observed in patients crossed over from placebo after 16 weeks. |
| Lipid-lowering drugs | ||||
| FOURIER-OLE (NCT03080935) | Phase 3, R, OLN = 6635 patients with ASCVD and LDL-C ≥70 mg/dL completing the FOURIER trial (3355 randomized to evolocumab and 3280 to placebo)FU: 5 years | Evolocumab 120 mg every 2 weeks or 420 mg monthly vs. placebo | Incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected. | At 12 weeks, median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C <40 mg/dL on evolocumab. Incidences of serious adverse events, did not exceed those for placebo-treated patients during the parent study and did not increase over time. |
| RACING (NCT03044665) | OL, R, PA, non-inferiorityN = 3780 patients with ASCVD (MI, ACS, coronary revascularization, and other arterial revascularization procedures, ischaemic stroke, or PADFU: 3 years | Rosuvastatin 10 mg QD with ezetimibe 10 mg QD vs. high-intensity statin monotherapy (rosuvastatin 20 mg QD) | 3-year composite of CV death, major CV events, or nonfatal stroke, in the intention-to-treat population with a non-inferiority margin of 2.0% | The primary endpoint occurred in 9.1% in the combination group (CG) and 9.9% in the high-intensity statin monotherapy group (MG). LDL-C levels <70 mg/dL at 1–3 years were observed in 72–75% of patients in the CG, and 55–60% MG (all P < 0.0001). Discontinuation or dose reduction of the study drug by intolerance was observed in 4.8% and 8.2%, respectively (P < 0.0001) |
| Polypill | ||||
| SECURE (NCT02596126) | Phase 3, R, PA, OLN = 2499 with previous MI | Cardiovascular polypill containing aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg) or usual care for 36 months | CV, nonfatal type 1 MI, nonfatal ischaemic stroke, or urgent revascularization | Treatment with this polypill within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse CV events than usual care |
| SGLT2 inhibitors | ||||
| DELIVER (NCT03619213) | Phase 3, R, DB, PCN = 6263 with HF and LVEF >40% and NT-proBNP ≥300 pg/mL or ≥600 pg/mLFU: 2.3 years | Dapagliflozin (10 mg QD) or matching placebo, in addition to usual therapy | Composite of worsening HF (defined as either an unplanned hospitalization for HF or an urgent visit for HF) or cardiovascular death, as assessed in a time-to-event analysis | The primary outcome occurred less in the dapagliflozin than in the placebo group (16.4% vs. 19.5%; P < 0.001). Worsening HF (11.8% vs. 14.5% HR, 0.79; 0.69–0.91), CV death (7.4% vs. 8.3%; HR, 0.88; 0.74–1.05) and total events and symptom burden were lower in the dapagliflozin group than in the placebo group. |
References are presented in Supplementary material online, Table S1.
ADVOR, Acetazolamide in Decompensated Heart Failure With Volume OveRload; AXIOMATIC-SSP, Antithrombotic Treatment With Factor XIa Inhibition to Optimize Management of Acute Thromboembolic Events for Secondary Stroke Prevention; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; FOURIER-OLE, FOURIER Open-Label Extension; HELIOS; A, HELIOS-A, A Study of Vutrisiran (ALN-TTRSC02) in Patients With Hereditary Transthyretin Amyloidosis; INVICTUS, INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies; PACIFIC-AF, Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation; PACIFIC-AMI; Study to Gather Information About the Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack; PACIFIC-Stroke, Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke; RACING, RAndomised Comparison of Efficacy and Safety of lipid lowerING with statin mono-therapy vs. statin–ezetimibe combination for high-risk cardiovascular disease; SECURE, Secondary Prevention of Cardiovascular Disease in the Elderly Trial; SURMOUNT-1, A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight; SURPASS, A Study of Tirzepatide (LY3298176) Compared With Dulaglutide on Major Cardiovascular Events in Participants With Type 2 Diabetes; VALOR-HCM, A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy.
AC, active-controlled; ACS, acute coronary syndrome; ASAT, abdominal subcutaneous adipose tissue; BARC, Bleeding Academic Research Consortium; CI, confidence interval; CVD, cardiovascular disease; DB, double-blind; HbA1c, glycated haemoglobin; HR, hazard ratio; MI, myocardial infarction; MRI, magnetic resonance imaging; MRI-PDFF, MRI-proton density fat fraction; OL, open-label; NT-proBNP, N-terminal pro B-type natriuretic peptide; PA, parallel assignment; PAD, peripheral artery disease; PC, placebo-controlled; PCI, Percutaneous coronary intervention; PG, parallel-group; Q3M, every 3 months; R, randomized; TIA, transient ischaemic attack; VAT, volume of visceral adipose tissue.