Clinical trial NCT02389946: Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in Subjects With Coronary Artery Lesions
Official title: BIOTRONIK - A Prospective Randomized Multicenter Study to Assess the SaFety and Effectiveness of the Orsiro SiroLimus Eluting Coronary Stent System in the Treatment Of Subjects With up to Three De Novo or Restenotic Coronary Artery Lesions - V
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Coronary Artery Disease
Atherosclerosis, Coronary
Myocardial Ischemia
Ischemic Heart Disease
Acute Coronary Syndrome
Angina Pectoris
Keywords: Drug eluting coronary stents
Sirolimus
Bioabsorbable polymer
DES
Lead sponsor: Biotronik, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Biotronik AG
name: Baim Institute for Clinical Research
name: Medstar Health Research Institute
First posted: 2015-03-17
Enrollment: 1334
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to assess the safety and efficacy of the Orsiro Sirolimus Eluting Coronary Stent System in the treatment of subjects with up to three native de novo or restenotic (standard PTCA only) coronary artery lesions compared to the Xience coronary stent system.

Detailed description: The BIOTRONIK BIOFLOW-V clinical trial is a prospective, multicenter, randomized, controlled trial combining data on the randomized subjects with data from two historical studies by employing a Bayesian approach.

Subjects with CAD that qualify for PCI with stenting will be screened per the protocol inclusion and exclusion criteria to achieve a total of up to 1,400 randomized subjects. Eligible subjects will be randomized in a 2:1 ratio, stratified by study center, to undergo percutaneous coronary revascularization with either the Orsiro Sirolimus Eluting Stent System (treatment group) or the Xience Everolimus Eluting Stent System (control group).

Subjects may receive treatment of up to three target lesions, one or two target lesions per target vessel, for a maximum of two target vessels. The target lesion(s) must be de novo or restenotic lesion(s) of ≤ 36 mm in length in native coronary artery(ies), with a reference vessel diameter of 2.25-4.0 mm. Treatment of restenotic lesions is allowed provided that the target lesion was previously treated with PTCA only. All treatment with study stents is to be performed during a single index procedure. Note: Concurrent treatment of non-target lesions during the index procedure is not allowed.

Randomized subjects will have clinical follow-up at 1 month, 6 months, 12 months and at 2, 3, 4 and 5 years following the index procedure.

To assess the non-inferiority of the Orsiro stent compared to the Xience stent, BIOFLOW-V randomized subjects will be combined with historical subjects from the BIOFLOW-II and BIOFLOW-IV randomized trials employing a Bayesian approach. Only subjects who meet all clinical and angiographic eligibility criteria of the BIOFLOW-V trial will be included in the analysis.

Eligibility criteria: Inclusion Criteria:

1. Subject is ≥18 years or the minimum age required for legal adult consent in the country of enrollment.
2. Subject is an acceptable candidate for PCI.
3. Subject is an acceptable candidate for CABG.
4. Subject has clinical evidence of ischemic heart disease, stable or unstable angina pectoris or documented silent ischemia.
5. Subject is eligible for dual anti-platelet therapy treatment with aspirin plus either, clopidogrel, prasugrel, ticagrelor or ticlopidine.
6. Subject has provided written informed consent.
7. Subject is willing to comply with study follow-up requirements.

Each target lesion/vessel must meet all of the following angiographic criteria for the subject to be eligible for the trial:

1. Subject has up to three target lesions in up to two separate target vessels (two target lesions in one vessel and one target lesion in a separate vessel).
2. Target lesion must be de novo or restenotic lesion in native coronary artery; restenotic lesion must have been treated with a standard PTCA only.
3. Target lesion must be in major coronary artery or branch (target vessel).
4. Target lesion must have angiographic evidence of ≥ 50% and \< 100% stenosis (by operator visual estimate). If the target lesion is \< 70% stenosed, clinical evidence of ischemia by positive functional study, CT, electrocardiography, FFR, or post infarct angina.
5. TIMI flow \> 1.
6. Target lesion must be ≤ 36 mm in length by operator visual estimate.
7. Target vessel RVD of 2.25-4.0 mm by operator visual estimate.
8. Target lesion must be treatable with a maximum of two overlapping stents.

Exclusion Criteria:

1. Subject has clinical symptoms and/or electrocardiogram (ECG) changes consistent with acute ST elevation myocardial infarction (STEMI) within 72 hours prior to the index procedure. Hemodynamically stable non-STEMI (NSTEMI) subjects are eligible for study enrollment.
2. Subject is hemodynamically unstable.
3. Subject is pregnant and/or breastfeeding or intends to become pregnant during the duration of the study.
4. Subject has a known allergy to contrast medium that cannot be adequately pre-medicated, or any known allergy to thienopyridine, aspirin, both heparin and bivalirudin, L-605 cobalt-chromium (Co-Cr) alloy or one of its major elements (cobalt, chromium, tungsten and nickel), acrylic, fluoropolymers, silicon carbide, PLLA, sirolimus or everolimus.
5. Revascularization of any target vessel within 9 months prior to the index procedure or previous PCI of any non-target vessel within 30 days prior to the index procedure.
6. Planned treatment of a lesion not meeting angiographic inclusion and exclusion criteria during the index procedure or after the index procedure.
7. Planned surgery within 6 months of index procedure unless dual antiplatelet therapy can be maintained throughout the peri-surgical period.
8. History of a stroke or transient ischemic attack (TIA) within 6 months prior to the index procedure.
9. Subjects with active bleeding disorders, active coagulopathy, or any other reason, who are ineligible for DAPT.
10. Subject will refuse blood transfusions.
11. Subject has documented left ventricular ejection fraction (LVEF) \< 30% within 90 days prior to the index procedure.
12. Subject is dialysis-dependent.
13. Subject has impaired renal function (i.e., blood creatinine \> 2.5 mg/dL or 221 μmol/L determined within 7 days prior to the index procedure).
14. Subject has leukopenia (i.e. \< 3,000 white blood cells/mm3), thrombocytopenia (i.e. \< 100,000 platelets/mm3) or thrombocytosis (i.e. \> 700,000 platelet/mm3).
15. Subject is receiving oral or intravenous immunosuppressive therapy (inhaled steroids are permitted), or has known life-limiting immunosuppressive or autoimmune disease (e.g., human immunodeficiency virus, systemic lupus erythematosus; diabetes mellitus is permitted).
16. Subject is receiving chronic anticoagulation (e.g. coumadin, dabigatran, apixaban, rivaroxaban or any other agent).
17. Subject has life expectancy of \< 1 year.
18. Subject is participating in another investigational (medical device or drug) clinical study. Subjects may be concurrently enrolled in a post-market study, as long as the post-market study device, drug or protocol does not interfere with the investigational treatment or protocol of this study.
19. In the investigator's opinion, subject will not be able to comply with the follow-up requirements.

Subjects will be excluded from the trial if any of the target lesions/vessels meets any of the following angiographic criteria:

1. Target lesion is located within a saphenous vein graft or arterial graft.
2. Target lesion is a restenotic lesion that was previously treated with a bare metal or drug eluting stent (in-stent restenosis).
3. Target lesion has any of the following characteristics:

   1. Lesion location is within the left main coronary artery, or within 3 mm of the origin of the left anterior descending (LAD) or left circumflex (LCX).
   2. Involves a side branch of \> 2.0 mm in diameter. Note: Lesions within 3 mm of the origin of the right coronary artery may be treated.
4. Target vessel/lesion is excessively tortuous/angulated or is severely calcified, that would prevent complete inflation of an angioplasty balloon. This assessment should be based on visual estimation.
5. Target vessel has angiographic evidence of thrombus.
6. Target lesion is totally occluded (100% stenosis).
7. Target vessel was treated with brachytherapy any time prior to the index procedure.

Primary outcomes:
measure: Percentage of Participants With Target Lesion Failure (TLF) at 12 Months Post-Index Procedure by Bayesian Estimation
timeFrame: 12-Months
Secondary outcomes:
measure: Number of Lesions With Device Success
timeFrame: Hospital Discharge (6-24 hours post-index procedure)
measure: Number of Lesions With Lesion Success
timeFrame: Hospital Discharge (6-24 hours post-index procedure)
measure: Number of Participants With Procedure Success
timeFrame: Hospital Discharge (6-24 hours post-index procedure)
measure: Number of Participants With Myocardial Infarction
timeFrame: Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years
measure: Number of Participants With Myocardial Infarction or Cardiac Death
timeFrame: Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years
measure: Number of Participants With MACE and Individual MACE Components
timeFrame: Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years
measure: Number of Participants With TLF and Individual TLF Components
timeFrame: Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years
measure: Number of Participants With Target Vessel Failure (TVF) and Individual TVF Components
timeFrame: Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years
measure: Number of Participants With Stent Thrombosis
timeFrame: 24 hours, 30 days, 1 year, and 5 years post-index procedure
Other outcomes:
Locations:
city: Fairhope
country: United States
state: Alabama
city: Concord
country: United States
state: California
city: La Mesa
country: United States
state: California
city: Laguna Hills
country: United States
state: California
city: Mission Viejo
country: United States
state: California
city: Washington
country: United States
state: District of Columbia
city: Clearwater
country: United States
state: Florida
city: Hollywood
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Urbana
country: United States
state: Illinois
city: Fort Wayne
country: United States
state: Indiana
city: Baltimore
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Bay City
country: United States
state: Michigan
city: Detroit
country: United States
state: Michigan
city: Lansing
country: United States
state: Michigan
city: Pontiac
country: United States
state: Michigan
city: Rochester
country: United States
state: Michigan
city: Troy
country: United States
state: Michigan
city: Ypsilanti
country: United States
state: Michigan
city: Minneapolis
country: United States
state: Minnesota
city: Omaha
country: United States
state: Nebraska
city: Hackensack
country: United States
state: New Jersey
city: Neptune
country: United States
state: New Jersey
city: Newark
country: United States
state: New Jersey
city: New York
country: United States
state: New York
city: New York
country: United States
state: New York
city: New York
country: United States
state: New York
city: Asheville
country: United States
state: North Carolina
city: Greensboro
country: United States
state: North Carolina
city: Fargo
country: United States
state: North Dakota
city: Cincinnati
country: United States
state: Ohio
city: Cleveland
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Elyria
country: United States
state: Ohio
city: Toledo
country: United States
state: Ohio
city: Toledo
country: United States
state: Ohio
city: Portland
country: United States
state: Oregon
city: Butler
country: United States
state: Pennsylvania
city: Mechanicsburg
country: United States
state: Pennsylvania
city: Wynnewood
country: United States
state: Pennsylvania
city: York
country: United States
state: Pennsylvania
city: Providence
country: United States
state: Rhode Island
city: Greenville
country: United States
state: South Carolina
city: Rock Hill
country: United States
state: South Carolina
city: Knoxville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: McKinney
country: United States
state: Texas
city: Tyler
country: United States
state: Texas
city: Charlottesville
country: United States
state: Virginia
city: Virginia Beach
country: United States
state: Virginia
city: Charleston
country: United States
state: West Virginia
city: Adelaide
country: Australia
city: Genk
country: Belgium
city: Leuven
country: Belgium
city: Roeselare
country: Belgium
city: Calgary
country: Canada
state: Alberta
city: Aarhus
country: Denmark
city: Bad Segeberg
country: Germany
city: Berlin
country: Germany
city: Berlin
country: Germany
city: Hamburg
country: Germany
city: Minden
country: Germany
city: Neuss
country: Germany
city: Budapest
country: Hungary
city: Pécs
country: Hungary
city: Szeged
country: Hungary
city: Haifa
country: Israel
city: Jerusalem
country: Israel
city: Petach Tikva
country: Israel
city: Rehovot
country: Israel
city: Tel Aviv
country: Israel
city: Daegu
country: Korea, Republic of
city: Gwangju
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Breda
country: Netherlands
city: Eindhoven
country: Netherlands
city: Nieuwegein
country: Netherlands
city: Auckland
country: New Zealand
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Malaga
country: Spain
city: Sevilla
country: Spain
city: Lausanne
country: Switzerland
city: Zurich
country: Switzerland
city: Zurich
country: Switzerland
Study officials:
affiliation: Medstar Health Research Institute
name: Ron Waksman, MD
role: STUDY_CHAIR
affiliation: Piedmont Heart Institute
name: David Kandzari, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Catharina Ziekenhuis
name: Jacques Koolen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Doros G, Massaro JM, Kandzari DE, Waksman R, Koolen JJ, Cutlip DE, Mauri L. Rationale of a novel study design for the BIOFLOW V study, a prospective, randomized multicenter study to assess the safety and efficacy of the Orsiro sirolimus-eluting coronary stent system using a Bayesian approach. Am Heart J. 2017 Nov;193:35-45. doi: 10.1016/j.ahj.2017.08.001. Epub 2017 Aug 5.
citation: Kandzari DE, Mauri L, Koolen JJ, Massaro JM, Doros G, Garcia-Garcia HM, Bennett J, Roguin A, Gharib EG, Cutlip DE, Waksman R; BIOFLOW V Investigators. Ultrathin, bioresorbable polymer sirolimus-eluting stents versus thin, durable polymer everolimus-eluting stents in patients undergoing coronary revascularisation (BIOFLOW V): a randomised trial. Lancet. 2017 Oct 21;390(10105):1843-1852. doi: 10.1016/S0140-6736(17)32249-3. Epub 2017 Aug 26.
citation: Kandzari DE, Koolen JJ, Doros G, Massaro JJ, Garcia-Garcia HM, Bennett J, Roguin A, Gharib EG, Cutlip DE, Waksman R; BIOFLOW V Investigators. Ultrathin Bioresorbable Polymer Sirolimus-Eluting Stents Versus Thin Durable Polymer Everolimus-Eluting Stents. J Am Coll Cardiol. 2018 Dec 25;72(25):3287-3297. doi: 10.1016/j.jacc.2018.09.019. Epub 2018 Sep 23.
citation: Roguin A, Kandzari DE, Marcusohn E, Koolen JJ, Doros G, Massaro JM, Garcia-Garcia HM, Bennett J, Gharib EG, Cutlip DE, Waksman R. Subgroup Analysis Comparing Ultrathin, Bioresorbable Polymer Sirolimus-Eluting Stents Versus Thin, Durable Polymer Everolimus-Eluting Stents in Acute Coronary Syndrome Patients. Circ Cardiovasc Interv. 2018 Oct;11(10):e007331. doi: 10.1161/CIRCINTERVENTIONS.118.007331.
citation: Hemetsberger R, Abdelghani M, Toelg R, Garcia-Garcia HM, Farhan S, Mankerious N, Elbasha K, Allali A, Windecker S, Lefevre T, Saito S, Kandzari D, Waksman R, Richardt G. Complex vs. non-complex percutaneous coronary intervention with newer-generation drug-eluting stents: an analysis from the randomized BIOFLOW trials. Clin Res Cardiol. 2022 Jul;111(7):795-805. doi: 10.1007/s00392-022-01994-4. Epub 2022 Feb 25.
citation: Hemetsberger R, Abdelghani M, Toelg R, Mankerious N, Allali A, Garcia-Garcia HM, Windecker S, Lefevre T, Saito S, Slagboom T, Kandzari D, Koolen J, Waksman R, Richardt G. Impact of Coronary Calcification on Clinical Outcomes After Implantation of Newer-Generation Drug-Eluting Stents. J Am Heart Assoc. 2021 Jun 15;10(12):e019815. doi: 10.1161/JAHA.120.019815. Epub 2021 May 29.
citation: Dan K, Garcia-Garcia HM, Kolm P, Windecker S, Saito S, Kandzari DE, Waksman R. Comparison of Ultrathin, Bioresorbable-Polymer Sirolimus-Eluting Stents and Thin, Durable-Polymer Everolimus-Eluting Stents in Calcified or Small Vessel Lesions. Circ Cardiovasc Interv. 2020 Sep;13(9):e009189. doi: 10.1161/CIRCINTERVENTIONS.120.009189. Epub 2020 Sep 8.
citation: Toelg R, Slagboom T, Waltenberger J, Lefevre T, Saito S, Kandzari DE, Koolen J, Richardt G. Individual patient data analysis of the BIOFLOW study program comparing safety and efficacy of a bioresorbable polymer sirolimus eluting stent to a durable polymer everolimus eluting stent. Catheter Cardiovasc Interv. 2021 Nov 1;98(5):848-856. doi: 10.1002/ccd.29254. Epub 2020 Sep 5.
citation: Kandzari DE, Koolen JJ, Doros G, Garcia-Garcia HM, Bennett J, Roguin A, Gharib EG, Cutlip DE, Waksman R; BIOFLOW V Investigators. Ultrathin Bioresorbable-Polymer Sirolimus-Eluting Stents Versus Thin Durable-Polymer Everolimus-Eluting Stents for Coronary Revascularization: 3-Year Outcomes From the Randomized BIOFLOW V Trial. JACC Cardiovasc Interv. 2020 Jun 8;13(11):1343-1353. doi: 10.1016/j.jcin.2020.02.019.
citation: Mattke S, Hanson M, Bentele M, Kandzari DE. Cost and Mortality Implications of Lower Event Rates After Implantation of an Ultrathin-Strut Coronary Stent Compared With a Thin-Strut Stent Over Four Years. Cardiovasc Revasc Med. 2020 Jul;21(7):835-842. doi: 10.1016/j.carrev.2019.12.018. Epub 2019 Dec 18.
citation: Mattke S, Hanson M, Dallmann AC, Bentele M. Health Economic Evaluation of an Ultrathin, Bioresorbable-Polymer Sirolimus-Eluting Coronary Stent Compared to a Thin, Durable-Polymer Everolimus-Eluting Stent. Cardiovasc Revasc Med. 2019 Sep;20(9):752-757. doi: 10.1016/j.carrev.2018.11.006. Epub 2018 Nov 20.