IN.PACT DEEP 2014.

Methods	Study design: randomized‐controlled trial Method of randomization: performed using blocks of sealed envelopes Blinding: participant‐blinded Exclusions postrandomization: 0 Losses to follow‐up: 4 (3 in DEB arm, 1 in PTA arm) Study enrollment period: September 2009 to July 2012 Cross‐over: 0
Participants	Country: 13 European centers Setting: hospital, multicenter Number of participants: 358 (DEB 239, PTA 119) Age (mean ± SD): 73.3 ± 8.2 years (DEB), 71.7 ± 9.9 years (PTA) Gender: male 74% Rutherford class: DEB: class 3: 0%, class 4: 14.2%, class 5: 84.1%, class 6: 1.7%; PTA: class 3: 0.8%, class 4: 17.6%, class 5: 77.3%, class 6: 4.2% ABI: DEB: 0.75 ± 0.4, PTA: 0.81 ± 0.44 Inclusion criteria: Age ≥ 18 years and ≤ 85 years Women of childbearing potential have a negative pregnancy test ≤ 7 days before the procedure and were willing to use a reliable method of birth control for the duration of study participation Rutherford category ≥ 4 Life expectancy > 1 year Exclusion criteria: Planned amputation Acute thrombosis Previously placed stents
Interventions	Uncoated balloon angioplasty: 119 participants Uncoated balloon angioplasty device: standard PTA, unspecified DEB: 239 participants DEB device: IN.PACT Amphirion (Medtronic) Drug used: paclitaxel (dose unknown) Vessels treated: infrapopliteal arteries Anticoagulation/platelets: preprocedure: ASA 100 mg at least 4 days prior to the index intervention, alternatively at least 500 mg loading dose prior to or within 2 hours postprocedure; clopidogrel 75 mg/day at least 4 days prior to the index intervention, alternatively at least 300 mg loading dose prior to or within 2 hours postprocedure (or ticlopidine, if required); the use of bivalirudin was allowed as an alternative to heparin Postprocedure: ASA 100 mg indefinitely and daily clopidogrel 75 mg (or ticlopidine, if required) for at least 1 month following the procedure. Prolonged antiplatelet therapy could be given at the discretion of the physician and should be considered after placement of stents Predilation before DEB: yes: 90.5% of procedures
Outcomes	Primary: TVR and late lumen loss at 12 months, composite end‐point of all‐cause death, major amputation and clinically driven TLV Secondary: Amputation‐free survival at 30 days, 3 and 6 months, 1, 2, 3, 4, and 5 years Rate of wound healing at 30 days, 6 months, 1 and 2 years Amputation‐free survival and wound healing at 6 months, 1 and 2 years Amputation‐free survival and resolved CLI at 6 months, 1 and 2 years Death, amputation, and clinically driven TLR at 30 days, 6 months, 1 and 2 years Primary sustained clinical improvement: an improvement shift in the Rutherford classification of 1 class in amputation‐free, clinically driven TLR‐free surviving participants at 1 year Secondary sustained clinical improvement: an improvement shift in the Rutherford classification of 1 class including the need for clinically driven TLR in amputation‐free surviving participants at 1 year QoL assessment by EQ‐5D at 6 months, 1 and 2 years vs. baseline Walking capacity assessment by WIQ at 6 months, 1 and 2 years, MAE at 30 days, 6 months, 1, 2, 3, 4, and 5 years Device success defined as the exact deployment of the device according to the instructions for use as documented with suitable imaging modalities and, in the case of digital subtraction angiography, in at least 2 different imaging projections Technical success defined as successful vascular access and completion of the endovascular procedure and immediate morphologic success with ≤ 50% residual diameter reduction of the treated lesion on completion angiography Procedural success defined as combination of technical success, device success, and absence of procedural complications For the angio cohort: improvement in 12 months of % DS of the target lesion assessed by QVA Days of hospitalization
Notes	It is unclear which vessels were treated and whether any participants required more than 1 treatment per limb Sponsor: Medtronic, Santa Rosa California
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"The randomization process was performed using blocks of sealed envelopes". The methodology for generating those randomization blocks was not specified
Allocation concealment (selection bias)	Low risk	"The randomization process was performed using blocks of sealed envelopes"
Blinding of participants and personnel (performance bias) All outcomes	High risk	"This trial is a 2:1 randomized, controlled, patient‐blinded multicentre trial". This implies that the operators were not blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Both wound and angiographic core laboratories were blinded to the assigned treatment"
Incomplete outcome data (attrition bias) All outcomes	High risk	"The low angiographic and wound imaging compliance may have limited the full assessment of this therapy"
Selective reporting (reporting bias)	High risk	The published protocol listed several unreported outcomes such as change in Rutherford category and QoL scores. The number of inflow lesions treated and how those lesions were managed not reported
Other bias	Low risk	The outcomes of the 5% of participants who received a stent not reported