BIOLUX P‐II.

Methods	Study design: randomized controlled trial Method of randomization: electronic case report form after successful wire passage through the target lesion Blinding: neither the participants nor the operators were blinded to the procedure Exclusions postrandomization: 0 exclusions after randomization Losses to follow‐up: 3 lost to follow‐up and 4 withdrew (DEB), 2 lost to follow‐up (PTA) Study enrollment period: July 2012 to June 2013 Cross‐over: 0
Participants	Country: Austria, Belgium, and Germany. Setting: 1 hospital in Austria, 2 in Belgium, and 3 in Germany Number of participants: 72 Age (mean ± SD): 72.9 ± 10.3 years (DEB), 69.6 ± 8.9 years (PTA) Gender: males: DEB 27 (75%), PTA 30 (83%) Rutherford class: DEB: class 2: 2.8%, class 3: 19.4%, class 4: 5.6%, class 5: 72.2%; PTA: class 2: 8.3%, class 3; 13.9%, class 4: 5.6%, class 5: 72.2% ABI (± SD): DEB: 0.8 ± 0.3, PTA: 0.7 ± 0.3 Inclusion criteria: Written informed consent Willing and able to comply with follow‐up evaluations Age ≥ 18 years Single or sequential de novo or restenotic lesions (stenosis ≥ 70% diameter reduction or occlusion) in the infrapopliteal arteries ≥ 30 mm. Lesions should not have extend beyond the ankle joint Maximum of 2 different vessels could be treated: successful wire crossing required for the first target vessel before randomization occurred Participant with PAD or CLI according to the current guidelines in need for urgent revascularization to relieve symptoms and improve walking capacity RVD 2 mm to 4 mm, based on visual estimation Inflow free from flow‐limiting lesion confirmed by angiography. People with flow‐limiting inflow lesions (> 50% stenosis) could be included if lesion(s) had been treated successfully before the index procedure, with a maximum residual stenosis of 30% per visual assessment At least 1 nonoccluded crural vessel with angiographically documented runoff to the foot Successful wire crossing of the lesion Exclusion criteria: Flow‐limiting (> 50% DS) inflow lesion proximal to target lesion, left untreated Failure to obtain < 30% residual stenosis in a pre‐existing hemodynamically significant (> 50% DS) inflow lesion (DEB or DES not allowed for the treatment of inflow lesions) Infrapopliteal lesions extending beyond the ankle joint and involving crural vessels Acute thrombus in the target vessel (e.g. complication of inflow lesion treatment) documented by angiogram, if not treated successfully prior to enrolment) Planned major amputation above the ankle of target limb, or any other planned major surgery within 30 days postprocedure Previous bypass surgery of target vessel Previously implanted stent in target lesion Hemorrhagic diathesis or coagulopathy or other disorders such as gastrointestinal ulcerations or cerebral disorders that would restrict prescription of dual antiplatelet therapy Hepatic failure, deep vein thrombosis, thrombophlebitis, systemic lupus erythematous, or taking immunosuppressant therapy. Acute MI ≤ 3 months Renal failure with a creatinine of ≥ 2.5 mg/dL, except people currently on regular dialysis Phenprocoumon intake, except for people treated for arterial fibrillation. For these people, phenprocoumon treatment could be interrupted and restarted after treatment with dual antiplatelet therapy for 4 weeks postprocedure Known allergy to contrast media used for angiography that could not be controlled by premedication with steroids, antihistamines, or both Allergy, intolerance, or hypersensitivity to paclitaxel or related compounds or to the delivery matrix BTHC, or both Comorbid conditions limiting life expectancy ≤ 1 year Under active treatment for cancer; people who had been successfully treated for cancer in the past could be included Participating in another clinical device trial where the primary endpoint had not yet been reached Pregnant, breastfeeding, or both or women who intend to become pregnant during the time of the study
Interventions	Uncoated balloon angioplasty: 36 participants (55 lesions) Uncoated balloon angioplasty device: uncoated Passeo‐18 PTA balloon catheter DEB: 36 participants (50 lesions) DEB device: Passeo‐18 LUX drug‐releasing PTA balloon catheter Drug used: paclitaxel 3 μg/mm2 balloon surface Vessels treated: infrapopliteal arteries Anticoagulation/platelets: dual antiplatelet therapy with ASA 100 mg/day to 325 mg/day and clopidogrel 75 mg/day for 1 month postprocedure and for 3 months in case of bailout stenting with a bare‐metal stenting Predilation before DEB: yes for DEB but not PTA
Outcomes	Primary: MAE, defined as all‐cause death, major amputation of target extremity, target lesion thrombosis, TLV and TVR at 30 days Performance: target lesion primary patency rate at 6 months, defined as < 50% restenosis in the target lesion assessed by QVA without TLR Secondary: Target lesion failure TVR Binary restenosis rate MAE rate, defined as all‐cause death, major amputation of target extremity, target lesion thrombosis, TLR and TVR at 6 months and 12 months Change in mean ABI Change in Rutherford classification QoL evaluation, assessed by EQ‐5D questionnaire Duplex‐based primary patency Procedural success, defined as successful vascular access, completion of endovascular procedure and immediate morphologic success with a residual stenosis < 30% Device success, defined as exact deployment according to instructions for use. Technical success, defined as device or procedural success without the occurrence of MAEs during the hospital stay Late lumen loss
Notes	Clinical follow‐up scheduled at 30 days, 6 months, and 12 months, and angiographic follow‐up at 6 months Sponsor: Biotronik AG
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was performed after successful wire passage through the lesion via the electronic case report form. Patients were allocated to DEB and PTA in a 1:1 ratio, with block sizes of 4 and 6"
Allocation concealment (selection bias)	Unclear risk	Insufficient details provided to assess allocation concealment bias adequately
Blinding of participants and personnel (performance bias) All outcomes	High risk	Neither the participants nor the operators were blinded to the procedure
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Quantitative vascular angiography (QVA) analysis was performed by an independent core laboratory that was blinded to the treatment, and all adverse events were adjudicated by an independent clinical events committee"
Incomplete outcome data (attrition bias) All outcomes	High risk	19% of the DEB arm either withdrew from the study or were lost to follow‐up at 12 months
Selective reporting (reporting bias)	High risk	All prespecified outcomes were reported in the paper or provided by the authors through electronic correspondence. However, the results were not stratified by the type of treated infrapopliteal vessels (i.e. anterior tibial, posterior tibial, or peroneal arteries). The authors also did not specify whether those participants with more than 1 target lesion (33.3% of people with DEB and 44.4% with PTA) had several target vessels and whether the outcomes differed by the number of treated lesions and vessels
Other bias	High risk	While no bailout stenting was required in either treatment arm, the authors had a relatively low technical success rate (defined as < 30% residual stenosis) in both arms (54.2% DEB, 59.6% PTA)