First-in-Human Study Using the SiroMax™ Sirolimus-Coated Balloon Catheter as a Percutaneous Transluminal Coronary Angioplasty (PTCA) Balloon Catheter to Treat Subjects Who Have Coronary Artery Disease (CAD) Involving In-Stent Restenosis (ISR) or an Unstented Lesion in a Small Coronary Vessel (DNSV).

This is a prospective, multicenter, open label clinical trial which is being conducted at up to 8 clinical sites outside the United States. Up to 60 subjects will be treated in the clinical trial.

The ISR arm will enroll and treat up to 30 subjects, and the DNSV arm will enroll and treat up to an additional 30 subjects. A subset of at least 15 subjects in the ISR arm will be enrolled in a pharmacokinetic (PK) sub-study to assess the elimination profile of the drug.

The primary safety endpoint is the incidence of device- and/or procedure-related Major Adverse Cardiac Events (MACEs) through 30 days, 6 months, and 12 months post-procedure, for which a MACE is defined as a composite of any of the following complications:

• Cardiac Death
• Non-fatal Myocardial Infarction
• Non-fatal stroke

The primary efficacy endpoint is the target lesion failure (TLF) rate at 6-months. TLF is defined as:

• Cardiac death
• Ischemia-driven target lesion revascularization (TLR)
• Target vessel myocardial infarction

All subjects will undergo angiographic assessment during the index procedure per standard of care. A maximum of one non-target lesion in a non-target vessel may be treated with commercially available devices during the study index procedure. The non-target lesion must be treated during the index procedure and deemed an angiographic success prior to enrollment and treatment of the target lesion.

Only one target lesion may be treated with the study device.

All enrolled subjects who receive a study device will be evaluated through hospital discharge and at 30 days, 3 months, 6 months, 12 months, then annually through 5 years post index procedure. Subjects in the PK sub-study will have an additional follow-up visit at 7 days post procedure.

Inclusion criteria

• Age ≥ 21 years
• Provided written informed consent
• If a woman of child-bearing potential, agrees to use a reliable method of contraception from the time of screening through 12 months after the index procedure
• Diagnosed with symptomatic ischemic heart disease, stable or unstable angina with signs of ischemia, silent ischemia, or a positive function test
• Eligible for percutaneous coronary intervention (PCI)
• Able to tolerate dual antiplatelet therapy with aspirin, plus either Clopidogrel, Prasugrel, or Ticagrelor
• Any non-target lesions to be treated during the index procedure have been successfully treated
• Meets the additional Inclusion criteria for the corresponding arm
• Target lesion > 50% and < 100% stenosed by QCA in symptomatic patients, and > 70% and < 100% stenosed in asymptomatic patients prior to lesion pre-treatment
• Distal TIMI grade flow of 3
• Target lesion must be ≤ 26mm length
• Successful pre-treatment of the target lesion
• Target lesion is within a native coronary artery or major branch
• Inclusion Criteria (Additional for ISR arm):
• Reference vessel diameter is ≥ 2.0 mm and ≤ 4.0 mm
• Restenosis of stented coronary artery (Includes BMS and DES). The target lesion may have been treated with no more than 2 stents
• Target lesion is within a previously placed BMS or DES and does not extend further than 5 mm beyond either the proximal or distal edge of the stent
• Confirmed stent expansion ≥ 80% of distal reference vessel diameter by angiography and there is no malposed stent struts
• Inclusion Criteria (Additional for PK Sub-Study):
• Eligible for treatment in the ISR arm with one of the ten largest device sizes
• Inclusion Criteria (Additional for DNSV arm):
• Reference vessel diameter is ≥ 2.0 mm and ≤ 2.75 mm

Exclusion criteria

• Pregnant or nursing patients
• Subject presents with NSTEMI and rising biomarkers, or ongoing chest pain or is hemodynamically unstable
• Subject with history of ST-elevation myocardial infarction (STEMI) within 30 days of the index procedure
• Subject with planned major surgery within 30 days following the index procedure
• Subject with planned treatment of lesion involving aorto-ostial location
• History of previous target vessel perforation
• Cardiogenic shock
• Patients with lesions requiring interventional treatment in more than two vessels
• Extensive peripheral vascular disease that precludes safe sheath insertion
• Ostial lesion or planned future treatments
• Diffuse disease distal to target lesion with impaired runoff
• Subject is considered not able to tolerate at least 30 seconds of coronary occlusion for the target lesion treated
• Previous PCI of target vessel within 6 months prior to the procedure
• Planned PCI of any vessel within 30 days post index procedure and/or planned PCI of the target vessel within 12 months post procedure
• Currently participating or planning to participate, within 24 months of the index procedure, in an investigational drug or device trial
• Patient is a recipient of a heart transplant
• Known hypersensitivity or contraindication to aspirin, heparin, bivalirudin, or contrast agent
• History of allergic reaction or sensitivity to sirolimus or other analogue or derivative
• Known hypersensitivity to excipients with phospholipid or related origins and Poly(lactic-co-glycolic acid) (PLGA)
• Platelet count <100,000 cells/mm3 or >700,000 cells/mm3 or a white blood cell count of <3,000 cells/mm3
• Known renal insufficiency (e.g. serum creatinine >2.5mg/dL, or creatinine clearance ≤30 mL/min), or subject on dialysis, or acute kidney failure confirmed by 50% increase of serum creatinine within 48 hours before procedure and/or decrease in urine output
• Subject with history of New York Heart Association (NYHA) class III or IV heart failure
• History of bleeding diathesis, active peptic ulcer or GI bleeding within prior 6 months or coagulopathy or will refuse blood transfusions
• Planned surgery that would cause interruption in recommended DAPT duration per current guidelines
• History of a stroke within 6 months prior to the index procedure
• Concurrent life conditions with a life expectancy of less than 24 months
• In Investigator's opinion, the patient is not a good candidate for the study
• Left ventricular ejection fraction < 30%
• Unprotected left main coronary artery disease with ≥ 50% stenosis
• Target lesion at a bifurcation Note: A target lesion near a bifurcation is allowed if only a single vessel (either main vessel or side branch) is to be treated
• Evidence of extensive thrombus or dissection in target lesion
• Chronic total occlusion (CTO) in target lesion
• >30% residual stenosis after pre-treatment of target lesion
• Target lesion is located in the left main or within any arterial or venous graft
• Target lesion is in a side branch that is "jailed" by a main vessel stent
• > 50% stenosis of an additional proximal lesion or clinically significant distal lesion (in a vessel >2.0mm RVD) to the target or non-target lesion
• Target vessel is excessively tortuous, defined as more than one bend > 90° to reach target lesion
• Exclusion Criteria (Additional for ISR arm):
• Target lesion is the 3rd or greater stent failure (i.e., more than two [2] layers of stent are present at any segment of the target lesion)
• Target vessel had any previous vascular brachytherapy treatment or is planned to undergo brachytherapy at index procedure
• If single-layer ISR, any previous treatment (other than balloon angioplasty alone) of the target vessel for restenosis If double-layer ISR, any treatment (other than balloon angioplasty alone) of the double-layer ISR restenosis
• Exclusion Criteria (Additional for PK Sub-Study):
• Any limus family (Zotarolimus, Everolimus, Sirolimus etc.) eluting device has been placed/used in any part of the body within 3 months prior to the index procedure including any non-target lesion treated during the index procedure
• The subject is taking or has taken within the last 3 months any limus family medication(s) for any reason
• Subject is taking strong CYP3A4 Inhibitors within 14 days before the index procedure or plans to take the strong inhibitors during the study period (Strong inhibitors include: cobicistat; ritonavir; indinavir and ritonavir; itraconazole; ketoconazole; lopinavir and ritonavir; paritaprevir and ritonavir and ombitasvir (and/or dasabuvir); posaconazole; saquinavir and ritonavir; tipranavir and ritonavir; elvitegravir and ritonavir; telithromycin; voriconazole; ceritinib; clarithromycin; idealalisib; nefazodone; nelfinavir)
• Subject is taking strong CYP3A4 Inducers within 14 days before the index procedure or plans to take the strong inducers during the study period (Strong inducers include apalutamide; carbamazepine; enzalutamide; ivosidenib; lumacaftor and ivacaftor; mitotane; phenytoin; rifampin; St. John's wort)
• Exclusion Criteria (Additional for DNSV arm):
• Type C lesion
• Calcified or angular target lesion which cannot be pre-dilated with high pressure balloons, scoring balloon or IVL
• In-stent restenosis