Creager 2011.

Methods	Study design: multi‐centre prospective double‐blind placebo‐controlled parallel‐group RCT Intention‐to‐treat: no; utilised "efficacy set", which includes all patients who were randomised and had at least 1 post‐randomisation treadmill exercise test; utilised last observation carried forward methods Countries: USA (27 sites), UK (4 sites), Germany (4 sites)
Participants	Number randomised: total N = 289 (low‐dose HIF‐1α n = 74; mid‐dose HIF‐1α n = 74; high‐dose HIF‐1α n = 65; placebo n = 76); "efficacy set": N = 273 (low‐dose HIF‐1α n = 69; mid‐dose HIF‐1α n = 71; high‐dose HIF‐1α n = 62; placebo n = 71) Losses to follow‐up and withdrawals: not reported; only report n = 16 with no follow‐up treadmill tests Age (mean years ± SD): 68.4 ± 8.4 (low‐dose 65.7; mid‐dose 68.8; high‐dose 66.7; placebo 66.2) Gender (M): low‐dose 78.4%; mid‐dose 78.4%; high‐dose 72.3%; placebo 72.4% Inclusion criteria: men and women 40 to 80 years of age; bilateral atherosclerotic PAD and IC ascertained by resting ABI ≤ 0.90 in the index leg (if arteries non‐compressible, TBI ≤ 0.70); PAD in non‐index leg confirmed by resting ABI ≤ 0.90, reduction in ABI by ≥ 20% after exercise if ABI at rest was > 0.90, or stenosis ≥ 50% as evidenced by duplex ultrasonography, magnetic resonance angiography, or computed tomographic angiography; catheter‐based angiography for diagnosis if necessary; PWT between 1 and 12 minutes on a graded exercise treadmill test and confirmation of PAD as a reason for claudication by a decrease in ABI in the index leg or ≥ 20% immediately after exercise; stable claudication symptom for at least 6 months; smoking status; exercise habits; other medical therapy for claudication; stable for 3 months before enrolment Exclusion criteria: aortoiliac disease limiting the inflow of blood to areas of the limb that were to receive study treatment injections (thighs and calves); type 1 diabetes mellitus; CLI defined as the presence of rest pain, non‐healing ulcers, or tissue loss; PAD‐specific surgical revascularisation within 6 months or an endovascular procedure within 3 months of enrolment; conditions other than PAD that could confound assessment of walking time such as angina, congestive heart failure, or chronic lung disease; cancer within the previous 5 years and not current with American Cancer Society‐recommended cancer screening tests; proliferative diabetic retinopathy and clinically significant abnormal haematological, renal, and hepatic laboratory values
Interventions	Treatment: Low‐dose HIF‐1α ‐ 2 × 10⁹ viral particles Ad2/HIF‐1α/VP16, 20 intramuscular injections to each leg (100 µL per injection for a total of 2.0 mL per limb) at predefined sites in the thigh (11 injections) and calf (9 injections) Mid‐dose HIF‐1α ‐ 2 × 10¹⁰ viral particles Ad2/HIF‐1‐α/VP16, as in manner of treatment above High‐dose HIF‐1α ‐ 2 × 10¹¹ viral particles Ad2/HIF‐1‐α/VP16, as in manner of treatment above Control: placebo, phosphate‐buffered saline, 10% sucrose, and 0.02% polysorbate 80, given in the same manner as treatment above
Outcomes	Follow‐up times: 3, 6, and 12 months Outcomes: PWT and COT (graded treadmill test, modified Gardner protocol), ABI, QoL (WIQ)
Notes	Study period: not reported NCT00117650
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information provided to determine random sequence generation; randomisation at a ratio of 1:1:1:1 per treatment group
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	Unclear risk	16/289 participants not included in efficacy set due to not having a treadmill test after baseline, but no discussion of other losses or dropouts
Selective reporting (reporting bias)	Low risk	All outcomes listed in the ClinicalTrials.gov protocol reported on appropriately
Other bias	Unclear risk	Power calculation required 75 participants in each arm for 80% power to detect a treatment effect of 1.5 minutes in the 26‐week change from baseline in PWT Data were collected and analysed by the sponsor, Genzyme Corp., manufacturer of Ad2/HIF‐1α/VP16