Mohler 2003.

Methods	Study design: phase I double‐blind placebo‐controlled dose‐escalating RCT Intention‐to‐treat: not specified Country: USA
Participants	Number randomised with IC: n = 18 (CI‐1023 n = 15 (4 × 10⁸ n = 3, 4 × 10⁸.⁵ n = 3, 4 × 10⁹ n = 3, 4 × 10⁹.⁵ n = 3, 4 × 10¹⁰ n = 3); placebo n = 3) Number randomised with CLI: n = 15 (CI‐1023 n = 13 (4 × 10⁸ n = 3, 4 × 10⁸.⁵ n = 3, 4 × 10⁹ n = 3, 4 × 10⁹.⁵ n = 3, 4 × 10¹⁰ n = 1); placebo n = 2) Losses to follow‐up and withdrawals with IC: n = 1 in CI‐1023 lost to follow‐up; n = 5 withdrew (n = 3 in CI‐1023; n = 2 in placebo) Losses to follow‐up and withdrawals with CLI: n = 5 (CI‐1023 n = 5; placebo n = 1) Age (mean years ± SD) with IC: not specified Age (mean years ± SD) with CLI: 73 ± 8 Gender (M) with IC: 78% Gender (M) with CLI: 67% Inclusion criteria with IC: men or women > 40 years of age; patent inflow (aorto‐iliac segments); angiographic evidence of > 35% stenosis involving infrageniculate vessels and disabling claudication; demonstrable ABI at rest < 0.90 and/or exercise ABI < 0.75 confirmed on 2 different occasions 2 days apart Exclusion criteria with IC: advanced or unstable medical disease; renal insufficiency; proliferative retinopathy; history of malignancy other than non‐melanoma skin cancers Inclusion criteria with CLI: atherosclerotic peripheral arterial disease (PAD); > 35 years of age; patent inflow and angiographic evidence of infra‐inguinal disease (> 50% stenosis) involving the common femoral, superficial femoral, popliteal artery or infrapopliteal vessels and ongoing rest pain or tissue loss (grades II and II of the Joint Council of the Society for Vascular Surgery and the North American Chapter of the International Society for Cardiovascular Surgery Classification comprising categories 4 and 5 with demonstrable resting ABI < 0.70 and exercise ABI < 0.60 confirmed on 2 different occasions 2 days apart) Exclusion criteria with CLI: advanced renal or liver disease; evidence of infection of any type, including adenovirus, hepatitis virus (A, B, or C), or HIV; ophthalmological exam indicative of retinopathy; history of malignancy other than non‐melanoma skin cancers; successful surgical or endoluminal revascularisation of lower extremity to be treated; unstable angina; coronary artery disease requiring immediate surgical or angioplasty intervention, or recent transmural MI or CVA; serious CNS, psychiatric, musculoskeletal, or immune disease
Interventions	Treatment: CI‐1023 (AdGVVEGF121.10), dose escalation from 4 × 10⁸ to 4 × 10¹⁰ particle units in half‐log increments with 1 week between each dosage group for safety; 1‐mL intramuscular injections into 20 sites of the ischaemic lower limb; anatomical region of administration varied dependent on location of disease and vascular anatomy Control: placebo diluent, in the same manner as treatment
Outcomes	Follow‐up times with IC: days 1, 7, 15, 30, 90, and 180 and 12 months Outcomes with IC: Safety parameters, Walking ability using Gardner protocol, ABI, Anti‐adenovirus neutralising antibodies, Adenoviral cultures, VEGF levels Follow‐up times with CLI: 1 year Outcomes with CLI: Safety parameters including gangrene and amputation, ABI
Notes	Study period: reported all 13 participants receiving CI‐1023 as 1 group, although different doses were received based on dose‐escalation schedule
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Insufficient information provided to determine randomisation sequence; protocol was altered due to participants' refusal of placebo over treatment, which could be evidence of improper random sequence generation and allocation concealment; at each week or dose, 3 participants were meant to receive treatment and 1 placebo; this was altered after 3 doses for above reasons
Allocation concealment (selection bias)	High risk	Insufficient information provided to determine randomisation sequence; protocol altered due to participants' refusal of placebo over treatment, which could be evidence of improper random sequence generation and allocation concealment; at each week or dose, 3 participants were meant to receive treatment and 1 placebo; this was altered after 3 doses for above reasons
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	High risk	Dropouts of all participants reported, but in CLI group, 5 of 15 participants withdrew or were lost to follow‐up (this left only 1 participant in the placebo arm), and 6 of 18 participants withdrew or were lost to follow‐up in the IC group
Selective reporting (reporting bias)	Low risk	All outcomes reported but no protocol identified
Other bias	High risk	Very few numbers in this study and only 2 participants in the control group for the CLI study; 3 for IC Major change in protocol: after first 3 dosing cohorts, protocol was modified to an open‐label format with no placebo arm because of refusal to participate due to placebo arm ‐ same for both IC and CLI studies