Kibbe 2016.

Methods	Study design: multi‐centre phase II double‐blind RCT Intention‐to‐treat: yes, used LOCF (last observation carried forward) Countries: USA, Korea
Participants	Number randomised: N = 52 (VM202 low‐dose n = 21; VM202 high‐dose n = 20; placebo n = 11) Losses to follow‐up and withdrawals: VM202 low‐dose n = 1, VM202 high‐dose n = 2, placebo n = 1; 3/21 (14.3%) did not complete study in VM202 low‐dose group, 3/20 (15.0%) did not complete study in VM202 high‐dose group, 3/11 (27.3%) did not complete study in placebo group; 1 person from each group withdrew; 1 person in the placebo group died, as did 1 person in the low‐dose group Age (mean years ± SD): VM202 low‐dose 65.9 ± 10.7; VM202 high‐dose 67.2 ± 10.9; placebo 64.3 ± 14.5 Gender (M): VM202 low‐dose 66.7%; VM202 high‐dose 65.0%; placebo 54.5% Inclusion criteria: 18 to 90 years old; CLI (Rutherford Class 4 to 5); deemed to be poor or suboptimal candidates for bypass graft surgery or endovascular revascularisation; ≥ 1 hallmark symptom of CLI (ischaemic rest pain, focal gangrene (< 3 cm)) Exclusion criteria: pregnant women; successful revascularisation procedure or sympathectomy within 12 weeks before study initiation; major amputation anticipated in the target leg within 4 weeks of the start of treatment; estimated life expectancy < 6 months; thromboangiitis obliterans; deep tissue ulcerations with bone or tendon exposure or clinical evidence of invasive infection uncontrollable by antibiotics; required > 81 mg per day aspirin; currently receiving immunosuppressive medications, COX‐1/COX‐2 inhibitor drugs, high‐dose steroids, chemotherapy, or radiation; history within 5 years or new finding of malignant neoplasm; New York Heart Association Class III or IV heart failure; history of stroke or myocardial infarction within the last 6 months; unstable angina or proliferative retinopathy; any of the following laboratory findings: positive HIV, human T‐lymphotrophic virus, hepatitis B or C
Interventions	Treatment VM202 (plasmid DNA expressing 2 isoforms of HGF) low‐dose ‐ 1 × 4 mg VM202 intramuscular injections, 16 total injections into the affected leg according to a schedule that targeted the vascular compartments corresponding to occluded segments, given on day 0 and again on day 14 (8 mg total), followed by saline on days 28 and 42 VM202 high‐dose ‐ 1 × 4 mg VM202, in the same manner as above, on day 0, and again on days 14, 28, and 42 (16 mg total) Control: placebo, saline, in the same manner as above, on days 0, 14, 28, and 42
Outcomes	Follow‐up times: days 14, 28, and 42, and 3, 6, 9, and 12 months Outcomes: Adverse events, Difference in pain severity measured by VAS between baseline and 9 months, Change in VAS, Ulcer healing, Skin perfusion by TcPO₂, ABI and TBI, Rutherford Classification, Quality of life score using VascuQoL, Amputation, Mortality during 12 months
Notes	Study period: July 2010 to July 2012 NCT01064440
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information provided to determine random sequence generation; described only as a "1:2:2 scheme to placebo, low‐dose or high‐dose"
Allocation concealment (selection bias)	Unclear risk	Insufficient information provided to determine allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Described as double‐blind and used placebo but did not describe how saline placebo was disguised for personnel
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information provided to determine blinding of outcome assessment
Incomplete outcome data (attrition bias) All outcomes	Low risk	Low risk of attrition bias, as all participants accounted for; ITT analysis and LOCF performed
Selective reporting (reporting bias)	Low risk	All outcomes listed in Methods reported on
Other bias	Unclear risk	Funding by ViroMed; 1 study author receives consulting fees from ViroMed but specified that sole responsibility for data, statistical analysis, and manuscript content lies with the study authors ‐ not the funders