P2Y12 Inhibitor-based Single Antiplatelet Therapy After a Short DAPT vs. Conventional DAPT Following PCI With a Polymer-free Drug-coated Stent for Unprotected Left Main Coronary Artery Disease (ULTRA-LM) (ULTRA-LM)

P2Y12 Inhibitor-based Single Antiplatelet Therapy After a Short Dual Antiplatelet Therapy vs. Conventional Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention With Biofreedom ULTRA Polymer-free Drug-coated Stent for Unprotected Left Main Coronary Artery Disease (ULTRA-LM)

The management of patients with unprotected left main coronary artery (LMCA) disease undergoing percutaneous coronary intervention (PCI) in contemporary interventional cardiology practice remains matter of intense debate. Particularly, the combination of the optimal drug-eluting stent (DES) selection and antiplatelet regimen for patients who require LMCA PCI remains undetermined.

Newest-generation thin-strut polymer-free drug-coated stents have the potential to further mitigate chronic inflammation and promote faster re-endothelialization. In the LEADERS FREE randomized trial, PCI with the early-generation BioFreedom (Biosensors International, Switzerland) thick-strut stainless-steel drug-coated stent group was associated with significantly lower rates of the primary safety endpoint, defined as a composite of cardiac death, myocardial infarction, or stent thrombosis at 12 months compared to bare-metal stents among 2,466 patients at high-risk of bleeding who received one-month dual antiplatelet therapy (DAPT), a difference driven by a significantly lower risk for clinically driven target-lesion revascularization. In the ONE-MONTH DAPT randomized study, which enrolled 3,020 patients with coronary artery disease considered for PCI for noncomplex lesions, the rates of the primary composite endpoint of cardiac death, nonfatal myocardial infarction, target vessel revascularization, stroke, or major bleeding within 12 months occurred similarly in patients treated with 1-month DAPT after PCI with early-generation thick-strut stainless-steel polymer-free drug-coated stent (BioFreedom, Biosensors International, Switzerland) and those treated with 6- to 12-month DAPT after newer-generation biodegradable polymer DES (Biomatrix, Biosensors International, Switzerland or Ultimaster, Terumo Corp., Japan) implantation. However, no dedicated randomized clinical trial to date has evaluated the safety and efficacy of newest-generation thinner-strut cobalt-chromium polymer-free drug-coated stents combined with a P2Y12 inhibitor-based SAPT strategy among patients undergoing highly complex PCI procedures, such as those treated for LMCA disease.

Recent evidence from a large-scale meta-analysis of several randomized clinical trials including >32'000 patients indicated that 1-3 months of DAPT followed by P2Y12 inhibitor single antiplatelet therapy (SAPT) after second-generation DES implantation was associated with lower risk for major bleeding and similar risk for adverse ischemic outcomes compared with conventional DAPT. These findings suggest that P2Y12 inhibitor SAPT following a short DAPT course (1-3 months) may represent a valuable treatment option for patients undergoing PCI with newer-generation DES compared to standard conventional 12 months DAPT, but this strategy has never been investigated in dedicated randomized clinical trials focused on patients at highest-risk for ischaemic events, such as patients undergoing LMCA PCI.

The ULTRA-LM randomized trial aims at filling this current gap of knowledge, which may have large impact on clinical practice and international guidelines. ULTRA-LM will be the first randomized clinical trial to investigate the safety and efficacy of a novel thin-strut cobalt-chromium BioFreedom Ultra polymer-free drug-coated stent (Biosensors International, Switzerland) combined with P2Y12 inhibitor-based single antiplatelet therapy among patients undergoing PCI for LMCA disease.

Study Overview

• Status: Not yet recruiting
• Conditions: Left Main Coronary Artery Stenosis
• Intervention / Treatment: Device: LMCA PCI with Biofreedom Ultra drug-coated stent (Biosensors International, Switzerland); Drug: Conventional DAPT; Drug: P2Y12 inhibitor-based SAPT after short DAPT

Detailed Description

1. Myocardial revascularization for significant left main coronary artery disease

   Significant left main coronary artery disease (LMCA) is observed in 5-7% of patients undergoing coronary angiography. Coronary revascularization for patients with LMCA disease with stenosis >50% and documented ischemia or FFR ≤0.80 for diameter stenosis <90%, is currently recommended with a class of recommendation I and level of evidence (LOE) A by the 2018 European Society of Cardiology (ESC) guidelines for myocardial revascularization (8). However, the optimal management of patients with LMCA disease requiring myocardial revascularization in contemporary clinical practice remains matter of debate.

2. Coronary artery bypass grafting vs. percutaneous coronary intervention for left main coronary artery disease

   The available evidence from randomized controlled trials (RCTs) and meta-analyses comparing coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) using drug-eluting stents (DESs) among patients with LMCA suggests equivalent results for the safety composite of death, MI, and stroke up to 5 years of follow-up (9). A significant interaction with time is notable, providing early benefit for PCI in terms of myocardial infarction (MI) and peri-interventional stroke, which is subsequently offset by a higher risk of spontaneous MI during long-term follow-up. The need for repeat revascularization is higher with PCI than with CABG. The EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) randomized trial compared CABG with PCI using new-generation DESs among 1,905 patients with significant LMCA (10). At 3 years of follow-up, the primary endpoint of death, stroke, or MI occurred with similar frequency in the CABG and PCI group (14.7% vs. 15.4%; HR 1.00, 95% CI 0.79-1.26, p=0.98). The pre-planned landmark analysis from 30 days to 3 years showed a significant difference for the primary endpoint in favour of CABG (7.9% vs. 11.5%, p=0.02). The NOBLE (Nordic-Baltic-British Left Main Revascularization Study) randomized trial compared CABG with PCI using new-generation biolimus-eluting stents among 1,201 patients with significant LM disease (mean SYNTAX score of 23) (11). At a median follow-up of 3.1 years, the primary endpoint of death, non-procedural MI, stroke, and repeat revascularization occurred more frequently in the PCI than the CABG group (29% vs. 19%; HR 1.48, 95% CI 1.11-1.96, p=0.007). A recent collaborative individual patient pooled analysis of RCTs including 11,518 patients reviewed the currently available evidence from RCTs comparing CABG with PCI for LMCA or multivessel disease (12). The primary outcome was all-cause mortality. In the overall cohort, CABG was associated with a significant survival benefit during a mean follow-up of 3.8±1.4 years (5-year all-cause mortality 11.2% after PCI vs. 9.2% after CABG; HR 1.20, 95% CI 1.06-1.37, p=0.0038). There was a linear trend for HRs of death increasing with increasing SYNTAX tertiles (p=0.0011 for trend). However, among 4,478 patients with LMCA, those randomly assigned to CABG or PCI with a mean follow-up of 3.4±1.4 years reported similar risks for the primary outcome all-cause mortality (PCI, 10.7% vs. CABG, 10.5%; HR 1.07, 95% CI 0.87-1.33, p=0.52) at 5 years. There were no significant differences in mortality between PCI and CABG in subgroup analyses according to SYNTAX scores. Nevertheless, in patients with a high SYNTAX score, a trend towards better survival was noted with CABG. The proportion of patients with a high SYNTAX score was limited in view of the inclusion criteria of the respective studies. Current evidence indicates that PCI is an appropriate alternative to CABG in LMCA and low-to-intermediate anatomical complexity (8). Among patients with LMCA and low anatomical complexity, there is evidence that the outcomes with respect to major clinical endpoints are similar for PCI and CABG, resulting in a class I recommendation. Among patients with LMCA and high anatomical complexity, the number of patients studied in RCTs is low due to exclusion criteria; the risk estimates and CIs are imprecise but suggest a trend towards better survival with CABG. Therefore, PCI in this setting cannot be endorsed as reflected by a class III recommendation. For PCI in LMCA with intermediate anatomical complexity, the previous class IIa recommendation was maintained in view of the incomplete 5-year follow-up of the two largest RCTs in this setting.

3. Percutaneous coronary intervention with drug-eluting stents for left main coronary artery disease

   The optimal DES therapy for patients with significant LMCA disease undergoing percutaneous coronary intervention (PCI) in contemporary practice remains undetermined (8). In the Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for Unprotected Coronary Left Main Lesions (ISAR-LEFT MAIN-2) (n=650) trial (13), the cumulative incidence of the primary endpoint, a composite of all-cause death, myocardial infarction, or target lesion revascularization was 17.5% in the thin-strut durable polymer zotarolimus-eluting stent group (Resolute, Medtronic, USA) and 14.3% in the thin-strut biocompatible durable polymer everolimus-eluting stent group (Xience®, Abbott Vascular, USA) (relative risk 1.26; 95% CI]: 0.85 to 1.85; p=0.25) at 12 months. In the EXCEL trial (10), the rates of the primary composite endpoint of all-cause death, stroke, or myocardial infarction, occurred similarly in patients undergoing PCI with the newer-generation thin-strut durable polymer everolimus-eluting stent (Xience®) and coronary artery bypass graft surgery (CABG) (22.0% vs. 19.2%, p=0.13) at 5 years. In the NOBLE trial (11), the rates of the primary composite endpoint of all-cause death, non-procedural myocardial infarction, any repeat coronary revascularization, and stroke, was 29% in patients undergoing PCI with a thick-strut biodegradable polymer biolimus-eluting stent (Biomatrix Flex®, Biosensors, Switzerland) versus 19% in patients undergoing CABG (HR 1.48, 95% CI 1.11-1.96, CABG significantly better than PCI, p=0.0066) at 5 years. In the Improved Drug Eluting stent for All-comers Left Main (IDEAL-LM) randomized clinical trial (14), the rate of the primary endpoint, a composite of all-cause death, MI, or clinically indicated target vessel revascularization at 2 years did not differ between patients undergoing PCI with a biodegradable polymer everolimus-eluting stent (Synergy®, Boston Scientific, USA) combined with 4-month dual antiplatelet therapy (DAPT) (14.6%) and those undergoing PCI with a durable polymer everolimus-eluting stent (Xience®, Abbott Vascular, USA) combined with 12-month DAPT (11.4%) (p=0.17). Newer-generation thin-strut polymer-free drug-coated stents have the potential to further mitigate chronic inflammation and promote faster re-endothelialization. No dedicated randomized clinical trial to date has evaluated the safety and efficacy of newest-generation polymer-free drug-coated stents for PCI in patients with LMCA disease.

4. Antiplatetelet therapy after percutaneous coronary intervention for left main coronary artery disease

   The 2018 ESC guidelines on myocardial revascularization recommend at least 6 (chronic coronary syndrome) and 12 (acute coronary syndrome) months of DAPT after PCI with newer-generation DES among patients with unprotected LMCA stenosis (8). A recent meta-analysis of five large-scale randomized clinical trials including a total of 32'145 patients, of whom 972 (3%) patients were treated for LMCA disease, indicated that 1-3 months of DAPT followed by P2Y12 inhibitor single antiplatelet therapy (SAPT) after second-generation DES implantation in patients with chronic and acute coronary syndromes was associated with lower risk for major bleeding (random-effects model: HR 0.63, 95% 0.45-0.86) and similar risk for stent thrombosis (random-effects model: HR 1.19, 95% CI 0.86-1.65), all-cause death (random-effects model: HR 0.85, 95% CI 0.70-1.03), myocardial infarction (random-effects model: HR 1.05, 95% CI 0.89-1.23), and stroke (random-effects model: HR 1.08, 95% CI 0.68-1.74) compared with conventional DAPT (15). These findings suggest that a P2Y12 inhibitor-based SAPT following a short DAPT course (1-3 months) may represent a preferable treatment option, which is associated with similar ischemic, but lower bleeding risk, for patients undergoing PCI with newer-generation DES compared to standard conventional 12 months DAPT. Importantly, there was no significant differences between P2Y12 inhibitor SAPT and conventional DAPT with respect to stent thrombosis (random-effects model: HR 1.19, 95% CI 0.86-1.65; p=0.302). Overall, the incidences of stent thrombosis with modern DESs used in trials included in the meta-analysis were low, ranging from 0.2% vs. 0.1% in the SMART-CHOICE trial (19), to 0.7% vs. 0.5% in the GLOBAL LEADERS (20) trial and 0.4% vs. 0.6% in the TWILIGHT (21) trial. In addition, there were no significant differences with respect to other ischemic outcomes such as all-cause death despite a trend towards benefits with P2Y12 inhibitor SAPT (random-effects model: HR 0.85, 95% CI 0.70-1.03; p=0.091), myocardial infarction (random-effects model: HR 1.05, 95% CI 0.89-1.23; p=0.567), and stroke (random-effects model: HR, 1.08; 95% CI 0.68-1.74; p=0.738), while there was a significant 37% reduction in the risk of major bleeding complications (random-effects model: HR, 0.63; 95% CI 0.39-1.01; p=0.004) with P2Y12 inhibitor SAPT compared to conventional DAPT, suggesting a net clinical benefit in favour of P2Y12 inhibitor SAPT. However, the safety and efficacy of a potent P2Y12 receptor inhibitor-based SAPT after highly complex PCI, such as PCI for LMCA disease, has not been investigated to date.

5. Newer-generation polymer-free drug-coated stents for percutaneous coronary intervention

The BioFreedom polymer-free drug-coated stent (Biosensors International, Switzerland) has potential to further mitigate chronic inflammation, promote faster re-endothelialization and reduce DAPT duration among patients undergoing PCI. In the LEADERS FREE randomized trial (16), which included 2,466 patients at high-risk of bleeding, the primary safety endpoint, defined as a composite of cardiac death, myocardial infarction, or stent thrombosis at 12 months, was 9.4% in the early-generation thick-strut stainless-steel drug-coated stent (BioFreedom, Biosensors International, Switzerland) group and 12.9% in the bare-metal-stent (BMS) group (risk difference, -3.6 percentage points; 95% CI, -6.1 to -1.0; hazard ratio, 0.71; 95% CI, 0.56-0.91; p<0.001 for noninferiority, p=0.005 for superiority). The rates of clinically driven target-lesion revascularization were 5.1% in the drug-coated stent group and 9.8% in the bare-metal stent group (risk difference, -4.8 percentage points; 95% CI, -6.9 to -2.6; hazard ratio, 0.50; 95% CI, 0.37-0.69; p<0.001). In the ONE-MONTH DAPT study (17), which enrolled 3,020 patients with coronary artery disease considered for PCI for noncomplex lesions, the rates of the primary composite endpoint of cardiac death, nonfatal myocardial infarction, target vessel revascularization, stroke, or major bleeding within 12 months occurred similarly in 5.9% of patients treated with 1-month DAPT after early-generation thick-strut stainless-steel polymer-free drug-coated stent (BioFreedom, Biosensors International, Switzerland) implantation and in 6.5% of patients treated with 6- to 12-month DAPT after biodegradable polymer DES (Biomatrix, Biosensors International, Switzerland or Ultimaster, Terumo Corp., Japan) implantation (absolute difference -0.7%; upper limit of one-sided 97.5% CI, 1.33%; p<0.001 for noninferiority). The occurrence of major bleeding was not different (1.7% vs. 2.5%; p=0.136). There was no difference in the occurrence of stent thrombosis (0.7% vs 0.8%; p=0.842). These findings confirm the safety and efficacy of a short one-month DAPT course after PCI of noncomplex lesions with the BioFreedom polymer-free drug-coated stent (Biosensors International, Switzerland) among all-comer patients, including high- and non-high-bleeding risk patients. BioFreedom Ultra (Biosensors International, Switzerland), the latest iteration of the BioFreedom drug-coated stent, is a thin-strut (84-88 μm) cobalt-chromium polymer-free biolimus-coated stent. In the LEADERS III trial (18), which included 401 patients at high-risk of bleeding with similar criteria than in the historical LEADERS-FREE trial and who received one-month DAPT, the BioFreedom Ultra drug-coated stent with a thin-strut cobalt-chromium stent platform was shown non-inferior to the original thick-strut stainless-steal BioFreedom drug-coated stent with regards to the primary safety endpoint, a composite of cardiac death, myocardial infarction, and definite/probable stent thrombosis, and superior to BMS with respect to the primary efficacy endpoint of clinically indicated target lesion revascularization at one-year follow-up in a propensity-matched comparison. The safety and efficacy of the novel thin-strut cobalt-chromium BioFreedom Ultra polymer-free drug-coated stent (Biosensors International, Switzerland) combined with a potent P2Y12 inhibitor SAPT among patients undergoing PCI for complex coronary lesions, such as patients with LMCA stenosis, have however not been investigated to date.

• Study Type: Interventional
• Enrollment (Estimated): 766
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Maëlle Achard, RN; Phone Number: +41795533553; Email: maelle.achard@hcuge.ch

Study Locations

• Switzerland
  • Zürich, Switzerland
    • Zurich University Hospital
    • Principal Investigator: Barbara Stähli, MD
    • Contact: Rahel Kesterke, RN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years.
• Patient with chronic or acute coronary syndrome (unstable angina, or non-ST-elevation acute coronary syndrome).
• Subject with significant unprotected (ostial, mid-shaft, or distal) LMCA stenosis who underwent successful LMCA PCI with ≥1 BioFreedom Ultra polymer-free drug-coated stent (Biosensors International, Switzerland) according to current ESC guidelines on myocardial revascularization and/or local Heart Team decision.
• Subject willing to participate and able to understand, read and sign the informed consent document before the planned procedure.

Exclusion Criteria:

• Contraindications to PCI and/or DES implantation.
• Inability to adhere to DAPT for at least 6 months.
• Patient already on DAPT.
• Patients on oral anticoagulation.
• Previous coronary artery bypass surgery.
• LMCA in-stent restenosis or stent thrombosis.
• Recent ST-elevation myocardial infarction <5 days prior to randomization.
• Cardiogenic shock/hemodynamic instability at the time of intervention and/or need for mechanical/pharmacologic hemodynamic support.
• Participation or planned participation in another clinical trial, except for observational registries.
• Life expectancy <1 year.
• Pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: P2Y12 inhibitor-based single antiplatelet therapy after a short DAPT strategy arm; Successful LMCA PCI with ≥1 BioFreedom Ultra polymer-free drug-coated stent (Biosensors International, Switzerland). P2Y12 inhibitor SAPT with any of the commercially available oral P2Y12 inhibitors (clopidogrel, ticagrelor, or prasugrel 10 mg) after a short DAPT course during 2 years after the index LMCA procedure. In patients with intended clopidogrel use, a platelet function or genetic test is mandatory before hospital discharge for patients with intended treatment with clopidogrel. In case of high on-treatment platelet reactivity or an ABCD-GENE score =/>10, patients treated with clopidogrel should be switched to either ticagrelor or prasugrel with corresponding on-label loading dose regimens, at the investigator's discretion. At the discretion of the investigator, aspirin will be discontinued after LMCA PCI, or continued during the hospital stay. In all cases, aspirin will be discontinued at latest at hospital discharge.	Device: LMCA PCI with Biofreedom Ultra drug-coated stent (Biosensors International, Switzerland); Successful LMCA PCI with ≥1 BioFreedom Ultra polymer-free drug-coated stent (Biosensors International, Switzerland).; Drug: P2Y12 inhibitor-based SAPT after short DAPT; Potent P2Y12 inhibitor-based SAPT (ticagrelor 90 mg bd, or prasugrel 5 or 10 mg od, at the discretion of the investigator) during 2 years. Aspirin stopped after LMCA or at latest at hospital discharge.
Active Comparator: Conventional DAPT strategy arm; Successful LMCA PCI with ≥1 BioFreedom Ultra polymer-free drug-coated stent (Biosensors International, Switzerland) DAPT combining aspirin and any of the commercially available oral P2Y12 receptor inhibitors (clopidogrel, ticagrelor, or prasugrel) during 6 or 12 months followed by aspirin-based SAPT. In patients with index ACS presentation and who have tolerated DAPT for 12 months without bleeding complications, a prolonged DAPT course with aspirin and ticagrelor 60 mg bd (clopidogrel or prasugrel allowed, if patient not eligible for treatment with ticagrelor) beyond 12 months may be considered in those patients with high thrombotic risk and without an increased risk for major or life-threatening bleeding, and those with moderately elevated thrombotic risk.	Device: LMCA PCI with Biofreedom Ultra drug-coated stent (Biosensors International, Switzerland); Successful LMCA PCI with ≥1 BioFreedom Ultra polymer-free drug-coated stent (Biosensors International, Switzerland).; Drug: Conventional DAPT; 6 to 12 months of DAPT combining aspirin (≥75 mg od) and a P2Y12 inhibitor (clopidogrel 75 mg od, ticagrelor 90 mg bd, prasugrel 5 or 10 mg od at the discretion of the investigator) followed by aspirin SAPT.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-oriented composite endpoint (POCE)	Composite of all-cause death, any non-fatal myocardial infarction, or any revascularization (PCI, or CABG)	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Net adverse clinical and major adverse cardiac (NACE)	Composite of all-cause death, any non-fatal myocardial infarction, any revascularization (PCI, or CABG), or Bleeding Academic Research Consortium (BARC)19 3 or 5 major bleeding	2 years
Device-oriented composite endpoint (DOCE)	Composite of cardiac death, target vessel myocardial infarction, or clinically indicated target lesion revascularization (PCI, or CABG)	2 years
All-cause death	Cardiac and non-cardiac death	2 years
Any non-fatal myocardial infarction	Periprocedural or spontaneous, target vessel-related, and non-target vessel-related myocardial infarction	2 years
Any revascularization	Any revascularization (PCI or CABG)	2 years
Target lesion revascularization	Clinically indicated and non-clinically indicated target lesion revascularization	2 years
Clinically indicated target vessel revascularization	Clinically indicated and non-clinically indicated target vessel revascularization	2 years
Definite stent thrombosis	Academic Research Consortium definite stent thrombosis	2 years
Definite or probable stent thrombosis	Academic Research Consortium definite or probable stent thrombosis	2 years
Bleeding Academic Research Consortium 3 or 5 major bleeding events	BARC 3 or 5 major bleeding complications	2 years
Bleeding Academic Research Consortium ≥2 major bleeding events	BARC ≥2 major bleeding complications	2 years

Collaborators and Investigators

• Sponsor: IGLESIAS Juan Fernando
• Collaborators: University of Bern
• Investigators: Principal Investigator: Juan F. Iglesias, MD, Geneva University Hospitals, Switzerland

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: December 4, 2022
• First Submitted That Met QC Criteria: December 13, 2022
• First Posted (Actual): December 14, 2022

Study Record Updates

• Last Update Posted (Actual): March 21, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Percutaneous coronary intervention; Dual antiplatelet therapy; Left main coronary artery disease; Drug-coated stent; Polymer-free drug-eluting stent; P2Y12 inhibitor-based single antiplatelet therapy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Coronary Stenosis
• Other Study ID Numbers: 2022-1204

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data will be shared upon reasonable request to the principal investigator after publication of the study primary and secondary endpoints.
• IPD Sharing Time Frame: After publication of the study primary and secondary endpoints.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No