The DES BTK Vascular Stent System vs PTA in Subjects With Critical Limb Ischemia (SAVAL)

A Randomized Trial Comparing the Drug-Eluting Stent (DES) Below-the-Knee (BTK) Vascular Stent System (DES BTK Vascular Stent System) vs Percutaneous Transluminal Angioplasty (PTA) Treating Infrapopliteal Lesions in Subjects With Critical Limb Ischemia

Single phased global, prospective, multicenter clinical trial designed to demonstrate a superior patency rate and acceptable safety in below the knee arteries with lesions treated with the DES BTK Vascular Stent System vs. percutaneous transluminal angioplasty (PTA).

Study Overview

• Status: Completed
• Conditions: Critical Limb Ischemia
• Intervention / Treatment: Combination product: Drug Eluting Stent - Below the Knee; Device: Standard PTA Control Arm

Detailed Description

A global, prospective, multicenter, 2:1 randomized trial evaluating the safety and effectiveness of the DES BTK Vascular Stent System compared to standard percutaneous transluminal angioplasty to treat infrapopliteal artery lesions in subjects with critical limb ischemia(CLI).

Approximately 201 subjects will be randomized/enrolled to support a 2:1 randomization.

• Study Type: Interventional
• Enrollment (Actual): 201
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Dendermonde, Belgium, 9200
    • AZ Sint-Blasius
  • Genk, Belgium, 3600
    • ZOL Genk (Ziekenhuis Oost-Limburg)
  • Gent, Belgium, 9000
    • UZ Gent (Universitair Ziekenhuis Gent)
• France
  • Nantes, France, 44000
    • CHU Nantes
  • Paris, France, 75015
    • Hôpital Européen Georges Pompidou
  • Paris, France, 75014
    • Hôpital Paris Saint Joseph
  • Toulouse, France, 31076
    • Clinique Pasteur
• Japan
  • Chiba-ken
    • Urayasu-shi, Chiba-ken, Japan, 279-0001
      • Tokyo Bay Urayasu Ichikawa Medical Center
  • Fukuoka
    • Kitakyushu, Fukuoka, Japan, 802-8555
      • Kokura Memorial Hospital
  • Hokkaido
    • Asahikawa-shi, Hokkaido, Japan, 078-8510
      • Asahikawa Medical University Hospital
  • Hyogo
    • Amagasaki, Hyogo, Japan, 660-8511
      • Kansai Rosai Hospital
  • Nara
    • Kashihara, Nara, Japan, 634-8522
      • Nara Medical University Hospital
  • Osaka
    • Kishiwada, Osaka, Japan, 596-8522
      • Kishiwada Tokushukai Hospital
  • Tokyo
    • Bunkyō-Ku, Tokyo, Japan, 113-8510
      • Tokyo Medical and Dental University, Medical Hospital
    • Meguro, Tokyo, Japan, 153-8515
      • Toho University Ohashi Medical Center
• Netherlands
  • Den Haag, Netherlands, 2566
    • HAGA Ziekenhuis (Haga Ziekenhuis van Den Haag)
• United States
  • Arkansas
    • Jonesboro, Arkansas, United States, 72401
      • St. Bernards Medical Center
    • Little Rock, Arkansas, United States, 72211
      • Arkansas Heart Hospital
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Colorado
    • Denver, Colorado, United States, 80220
      • Colorado VA
  • Florida
    • Bradenton, Florida, United States, 34205
      • Bradenton Cardiology
  • Louisiana
    • Bossier City, Louisiana, United States, 71111
      • Willis Knighton Bossier Medical Center - Grace Research, LLC
    • Houma, Louisiana, United States, 70360
      • Cardiovascular Institute of the South Clinical Research Corporation
  • Michigan
    • Grand Rapids, Michigan, United States, 49525
      • Advanced Cardiac & Vascular Centers for Amputation Prevention
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • United Heart and Vascular Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Teaneck, New Jersey, United States, 07666
      • Holy Name Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • New Mexico Heart Institute, PA
  • New York
    • New York, New York, United States, 10016
      • New York University Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • North Carolina
    • Cary, North Carolina, United States, 27518
      • Amputation Prevention Center of North Carolina
    • Raleigh, North Carolina, United States, 27610
      • Wake Medical Center
    • Raleigh, North Carolina, United States, 27607
      • NC Heart and Vascular Research, LLC
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43214
      • OhioHealth Research and Innovation Institute - Riverside Methodist Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • INTEGRIS Baptist Medical Center
  • Pennsylvania
    • Erie, Pennsylvania, United States, 16544
      • Saint Vincent Consultants in Cardiovascular Diseases at St. Vincent Hospital
  • Tennessee
    • Jackson, Tennessee, United States, 38305
      • Jackson-Madison County General Hospital
  • Texas
    • Austin, Texas, United States, 78756
      • Heart Hospital of Austin
    • Lubbock, Texas, United States, 79430
      • Texas Tech University Health
    • Plano, Texas, United States, 75093
      • THR Presbyterian Plano

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Subject is 18 years or older and has signed and dated the trial informed consent form (ICF)
2. Subject is willing and able to comply with the trial testing, procedures and follow-up schedule
3. Subject has chronic, symptomatic lower limb ischemia, determined by Rutherford categories 4 or 5 in the target limb, with wound(s) confined to toes/forefoot
4. Subject is a male or non-pregnant female. If female of child-bearing potential, and if sexually active must be using, or agree to use, a medically-acceptable method of birth control as confirmed by the investigator

Intra-procedure Inclusion Criteria:

1. Stenotic, restenotic or occlusive target lesion(s) located in the tibioperoneal trunk, anterior tibial, posterior tibial and/or peroneal artery(ies).
2. Target lesion(s) must be at least 4cm above the ankle joint
3. A single target lesion per vessel, in up to 2 vessels, in a single limb
4. Degree of stenosis ≥ 70% by visual angiographic assessment
5. Reference vessel diameter is between 2.5 - 3.25mm for phase A RCT
6. Total target lesion length (or series of lesion segments) to be treated is ≤ 70 mm for phase A RCT prior to the data monitoring committee's approval for stent overlap. (Note: Lesion segment(s) must be fully covered with one DES BTK stent, if randomized to stent)
7. Total target lesion length (or series of lesion segments) to be treated is ≤ 140 mm for phase A RCT after the data monitoring committee's approval for stent overlap (Note: Lesion segment(s) must be fully covered with up to two DES BTK stents, if randomized to stent)
8. Target vessel(s) reconstitute(s) at or above the stenting limit zone (4cm above the ankle joint)
9. Target lesion(s) is located in an area that may be stented without blocking access to patent main branches
10. Treatment of all above the knee inflow lesion(s) is successful prior to treatment of the target lesion
11. Guidewire has successfully crossed the target lesion(s)

Exclusion Criteria:

1. Life expectancy ≤ 1year
2. Stroke ≤ 90 days prior to the procedure date
3. Prior or planned major amputation in the target limb
4. Previous surgery in the target vessel(s) (including prior ipsilateral crural bypass)
5. Previously implanted stent in the target vessel(s)
6. Failed PTA of target lesion/vessel ≤ 60 days prior to the procedure date
7. Renal failure as measured by a GFR ≤ 30ml/min per 1.73m2, measured ≤ 30 days prior to the procedure date
8. Subject has a platelet count ≤ 50 or ≥ 600 X 103/µL ≤ 30 days prior to the procedure date
9. NYHA class IV heart failure
10. Subject has symptomatic coronary artery disease (ie, unstable angina)
11. History of myocardial infarction or thrombolysis ≤ 90 days prior to the procedure date
12. Non-atherosclerotic disease resulting in occlusion (eg, embolism, Buerger's disease, vasculitis)
13. Subject is currently taking Canagliflozin
14. Body Mass Index (BMI) <18
15. Active septicemia or bacteremia
16. Coagulation disorder, including hypercoagulability
17. Contraindication to anticoagulation or antiplatelet therapy
18. Known allergies to stent or stent components
19. Known allergy to contrast media that cannot be adequately pre-medicated prior to the interventional procedure
20. Known hypersensitivity to heparin
21. Subject is on a high dose of steroids or is on immunosuppressive therapy
22. Subject is currently participating, or plans to participate in, another investigational trial that may confound the results of this trial (unless written approval is received from the Boston Scientific study team)

Intra-procedure Exclusion Criteria

1. Angiographic evidence of intra-arterial acute/subacute thrombus or presence of atheroembolism
2. Treatment required in > 2 target vessels (Note: a target lesion originating in one vessel and extending into another vessel is considered 1 target vessel)
3. Treatment requires the use of alternate therapy in the target vessel(s)/lesion(s), (eg, atherectomy, cutting balloon, re-entry devices, laser, radiation therapy)
4. Aneurysm is present in the target vessel(s)
5. Extremely calcified lesions

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: DES BTK; Treatment with DES BTK	Combination product: Drug Eluting Stent - Below the Knee; Treatment arm with DES-BTK, starting with one size of the device - 3.5 mm X 80 mm
Active Comparator: Conventional PTA; Treatment with standard PTA	Device: Standard PTA Control Arm; The PTA device used must be market-released in the investigational center's geography and the size (ie, diameter, balloon length and catheter length) will be determined by the investigator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Primary Patency	Twelve-Month Primary Patency defined as a binary endpoint to be determined via duplex ultrasound (DUS) measuring flow at the 12-month follow-up visit, in the absence of clinically-driven target lesion revascularization (TLR) or bypass of the target lesion. Data table consists of the number of participants with flow as assessed by DUS.	12 months
Number of Participants Free From Major Adverse Events (MAE)	The primary safety endpoint assesses freedom from major adverse events (MAE) at 12 months post-procedure. (MAE is defined as: above ankle amputation in index limb; major re-intervention; and perioperative (30 day) mortality)	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Assisted Primary Patency	Assisted primary patency defined as the percentage (%) of lesions without clinically-driven TLR and those with clinically-driven TLR (not due to complete occlusion or by-pass) which show flow by DUS without restenosis.	12 months post procedure
Number of Participants With Clinically Driven Target Lesion Revascularization	Clinically-driven target lesion revascularization is defined as any surgical or percutaneous intervention to the target lesion after the index procedure if: Occurring within 5mm proximal or distal to the original treatment segment with diameter stenosis ≥50% by quantitative angiography and if participant has recurrent symptoms OR; In-lesion diameter stenosis less than 50% might also be considered a MAE by the CEC if the subject has recurrent symptoms. Recurrent symptoms are defined as having ≥ 1 change in Rutherford Classification or associated with decreased ABI/TBI of ≥20% or ≥ 0.15 in the treated segment.	12 months post procedure
Number of Participants With Major Amputation (Defined as Amputation of the Lower Limb at the Ankle Level or Above)	Rates of amputation of the lower limb at the ankle level or above	12 months post procedure
Participant Quality-of-Life Changes Via EuroQol 5 Dimension (EQ-5D) Questionnaire.	The EQ-5D is a descriptive system of health-related quality-of-life states consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) each of which can take 1 of 5 responses. The responses record 5 levels of severity (no problems/slight problems/moderate problems/severe problems/extreme problems) within a particular EQ-5D dimension). The levels are assigned a numeric code 1-5 (eg, 1= no problems and 5= extreme problems).	12 months post procedure
Participant Quality-of-Life Changes Via Vascular Quality of Life (VascuQol) Questionnaire.	Changes in quality of life is measured using the Vascular Quality of Life (VascuQol) questionnaire, which is a 25 item questionnaire used to measure the quality-of-life in patients with lower limb ischemia. The tool is sub-divided into 5 domains: pain, symptoms, activities, social and emotional.	12 months post procedure
Number of Participants With Baseline Wounds Assessed as Healed	Wounds assessed for healed status by Independent Wound Assessors, blinded to randomized treatment.	12 months post procedure
Number of Participants With Rate of Primary Sustained Clinical Improvement as Assessed by Changes in Rutherford Classification From Baseline	Endpoint determined to be a success when there is an improvement in Rutherford Classification of one or more categories as compared to pre-procedure without the need for repeat TLR. Rutherford Classifications: i. Category 0 - Asymptomatic ii. Category 1 - Mild claudication iii. Category 2 - Moderate claudication iv. Category 3 - Severe claudication v. Category 4 - Ischemic rest pain vi. Category 5 - Minor tissue loss - nonhealing ulcer, focal gangrene vii. Category 6 - Major tissue loss - extending above transmetatarsal (TM) level	12 months post procedure
Number of Participants With Major, Serious, Non-serious, Unanticipated, Device-related and Procedure-related Adverse Events	Adverse events (AEs) to be classified as major (defined as above ankle amputation of the index limb, major re-intervention (new bypass graft, jump/interposition graft, or thrombectomy/thrombolysis) and perioperative (30 day) mortality), serious, non-serious, unanticipated, procedure-related and device-related.	12 months post procedure
Number of Participants Who Were Admitted to the Hospital Within 30 Days After the Index Procedure.	Hospitalizations related to Critical Limb Ischemia (CLI) due to target lesion revascularization (TLR)/target vessel revascularization (TVR) or Target Limb Major Amputation or Procedure/Device related Adverse Events	Up to 30 days post procedure
Number of Participants With Hemodynamic Improvement	Hemodynamic improvement is defined as improvement of ankle-brachial index (ABI) by ≥0.10 or to an ABI ≥0.90 as compared to pre-procedure value without the need for repeat revascularization.	12 months post procedure

Collaborators and Investigators

• Sponsor: Boston Scientific Corporation
• Investigators: Principal Investigator: Jihad Mustapha, MD, Advanced Cardiac & Vascular Centers for Amputation Prevention; Principal Investigator: Hendrik van Overhagen, MD, HAGA Ziekenhuis (HagaZiekenhuis van Den Haag); Principal Investigator: Patrick Geraghty, MD, Washington University School of Medicine; Principal Investigator: Masato Nakamura, MD, PhD, Toho University Ohashi Medical Center - Division of Cardiovascular Medicine

Publications and helpful links

General Publications

• Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes FG, Gillepsie I, Ruckley CV, Raab G, Storkey H; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005 Dec 3;366(9501):1925-34. doi: 10.1016/S0140-6736(05)67704-5.
• Conte MS, Geraghty PJ, Bradbury AW, Hevelone ND, Lipsitz SR, Moneta GL, Nehler MR, Powell RJ, Sidawy AN. Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg. 2009 Dec;50(6):1462-73.e1-3. doi: 10.1016/j.jvs.2009.09.044. Epub 2009 Nov 7.
• Kolte D, Kennedy KF, Shishehbor MH, Abbott JD, Khera S, Soukas P, Mamdani ST, Hyder ON, Drachman DE, Aronow HD. Thirty-Day Readmissions After Endovascular or Surgical Therapy for Critical Limb Ischemia: Analysis of the 2013 to 2014 Nationwide Readmissions Databases. Circulation. 2017 Jul 11;136(2):167-176. doi: 10.1161/CIRCULATIONAHA.117.027625. Epub 2017 May 2.
• Scheinert D, Katsanos K, Zeller T, Koppensteiner R, Commeau P, Bosiers M, Krankenberg H, Baumgartner I, Siablis D, Lammer J, Van Ransbeeck M, Qureshi AC, Stoll HP; ACHILLES Investigators. A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results from the ACHILLES trial. J Am Coll Cardiol. 2012 Dec 4;60(22):2290-5. doi: 10.1016/j.jacc.2012.08.989.
• Spreen MI, Martens JM, Hansen BE, Knippenberg B, Verhey E, van Dijk LC, de Vries JP, Vos JA, de Borst GJ, Vonken EJ, Wever JJ, Statius van Eps RG, Mali WP, van Overhagen H. Percutaneous Transluminal Angioplasty and Drug-Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI) Trial. Circ Cardiovasc Interv. 2016 Feb;9(2):e002376. doi: 10.1161/CIRCINTERVENTIONS.114.002376.
• Kinlay S. Management of Critical Limb Ischemia. Circ Cardiovasc Interv. 2016 Feb;9(2):e001946. doi: 10.1161/CIRCINTERVENTIONS.115.001946.
• Elsayed S, Clavijo LC. Critical limb ischemia. Cardiol Clin. 2015 Feb;33(1):37-47. doi: 10.1016/j.ccl.2014.09.008.
• Conte MS. Critical appraisal of surgical revascularization for critical limb ischemia. J Vasc Surg. 2013 Feb;57(2 Suppl):8S-13S. doi: 10.1016/j.jvs.2012.05.114.
• Gray BH, Diaz-Sandoval LJ, Dieter RS, Jaff MR, White CJ; Peripheral Vascular Disease Committee for the Society for Cardiovascular Angiography and Interventions. SCAI expert consensus statement for infrapopliteal arterial intervention appropriate use. Catheter Cardiovasc Interv. 2014 Oct 1;84(4):539-45. doi: 10.1002/ccd.25395. Epub 2014 Jul 18.
• Popplewell MA, Davies HOB, Narayanswami J, Renton M, Sharp A, Bate G, Patel S, Deeks J, Bradbury AW. A Comparison of Outcomes in Patients with Infrapopliteal Disease Randomised to Vein Bypass or Plain Balloon Angioplasty in the Bypass vs. Angioplasty in Severe Ischaemia of the Leg (BASIL) Trial. Eur J Vasc Endovasc Surg. 2017 Aug;54(2):195-201. doi: 10.1016/j.ejvs.2017.04.020. Epub 2017 Jun 8.
• Sadaghianloo N, Jean-Baptiste E, Declemy S, Mousnier A, Brizzi S, Hassen-Khodja R. Percutaneous angioplasty of long tibial occlusions in critical limb ischemia. Ann Vasc Surg. 2013 Oct;27(7):894-903. doi: 10.1016/j.avsg.2013.02.008.
• Bosiers M, Scheinert D, Peeters P, Torsello G, Zeller T, Deloose K, Schmidt A, Tessarek J, Vinck E, Schwartz LB. Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive disease. J Vasc Surg. 2012 Feb;55(2):390-8. doi: 10.1016/j.jvs.2011.07.099. Epub 2011 Dec 14.
• Spreen MI, Martens JM, Knippenberg B, van Dijk LC, de Vries JPM, Vos JA, de Borst GJ, Vonken EPA, Bijlstra OD, Wever JJ, Statius van Eps RG, Mali WPTM, van Overhagen H. Long-Term Follow-up of the PADI Trial: Percutaneous Transluminal Angioplasty Versus Drug-Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia. J Am Heart Assoc. 2017 Apr 14;6(4):e004877. doi: 10.1161/JAHA.116.004877.
• de Weger VA, Beijnen JH, Schellens JH. Cellular and clinical pharmacology of the taxanes docetaxel and paclitaxel--a review. Anticancer Drugs. 2014 May;25(5):488-94. doi: 10.1097/CAD.0000000000000093. Erratum In: Anticancer Drugs. 2015 Feb;26(2):240.
• Ng VG, Mena C, Pietras C, Lansky AJ. Local delivery of paclitaxel in the treatment of peripheral arterial disease. Eur J Clin Invest. 2015 Mar;45(3):333-45. doi: 10.1111/eci.12407. Epub 2015 Feb 14.
• Dake MD, Van Alstine WG, Zhou Q, Ragheb AO. Polymer-free paclitaxel-coated Zilver PTX Stents--evaluation of pharmacokinetics and comparative safety in porcine arteries. J Vasc Interv Radiol. 2011 May;22(5):603-10. doi: 10.1016/j.jvir.2010.12.027. Epub 2011 Mar 17.
• Federman DG, Ladiiznski B, Dardik A, Kelly M, Shapshak D, Ueno CM, Mostow EN, Richmond NA, Hopf HW. Wound Healing Society 2014 update on guidelines for arterial ulcers. Wound Repair Regen. 2016 Jan-Feb;24(1):127-35. doi: 10.1111/wrr.12395. No abstract available.
• Banerjee S, Sarode K, Mohammad A, Gigliotti O, Baig MS, Tsai S, Shammas NW, Prasad A, Abu-Fadel M, Klein A, Armstrong EJ, Jeon-Slaughter H, Brilakis ES, Bhatt DL. Femoropopliteal Artery Stent Thrombosis: Report From the Excellence in Peripheral Artery Disease Registry. Circ Cardiovasc Interv. 2016 Feb;9(2):e002730. doi: 10.1161/CIRCINTERVENTIONS.115.002730. Erratum In: Circ Cardiovasc Interv. 2016 Oct;9(10):e000019. doi: 10.1161/HCV.0000000000000019.

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2018
• Primary Completion (Actual): April 21, 2022
• Study Completion (Actual): December 20, 2023

Study Registration Dates

• First Submitted: May 15, 2018
• First Submitted That Met QC Criteria: June 7, 2018
• First Posted (Actual): June 11, 2018

Study Record Updates

• Last Update Posted (Actual): July 1, 2024
• Last Update Submitted That Met QC Criteria: June 27, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Disease Attributes; Atherosclerosis; Peripheral Vascular Diseases; Chronic Disease; Peripheral Arterial Disease; Ischemia; Chronic Limb-Threatening Ischemia
• Other Study ID Numbers: S2348

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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