Belch 2011.

Methods	Study design: multi‐centre phase III double‐blind placebo‐controlled RCT Intention‐to‐treat: yes Countries: 30 countries
Participants	Number randomised: N = 525 (NV1FGF n = 259; placebo n = 266) Losses to follow‐up and withdrawals: N = 0 Age (mean years (range)): 70 years (50 to 95) (NV1FGF 71 (50 to 95); placebo 69 (50 to 92)) Gender (M): 70% (NV1FGF 69%; placebo 70%) Inclusion criteria: age > 50 years; CLI with ischaemic lesions (Fontaine stage IV) with diagnosis confirmed by at least 1 haemodynamic measurement (ankle pressure < 70 mmHg, toe pressure < 50 mmHg, or TcPO₂ < 30 mmHg) and by 1 imaging technique (angiography or doppler examination), and confirmed by vascular surgeons that participant was unsuitable for revascularisation; and to justify this decision to the independent adjudication panel, patent femoral artery inflow assessed by digital angiography, magnetic resonance, or CT angiography (doppler if previous angiography is available) < 6 months before first administration of study treatment; negative screening for cancer (including family history, complete physical examination of every system organ including the skin, haematological blood testing, chest radiography, stool haemoccult test, measurement of prostate‐specific antigen for men, and mammography and Papanicolaou test for women, and any investigation required by national guidelines for cancer screening) Exclusion criteria: previous major amputation of the leg to be treated; planned major amputation within the first month after randomisation; infected gangrene affecting the forefoot evidenced by imaging (radiography); CLI caused by Buerger’s disease; ulcers from venous or neuropathic origin if not associated with at least 1 ulcer of arterial origin; successful revascularisation procedure of the lower leg or any other successful treatment of the leg to be treated < 3 months before randomisation; uncontrolled blood pressure defined as systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg; severe comorbid disorder, not expected to survive longer than 12 months; acute cardiovascular events within 3 months before randomisation; active or proliferative retinopathy and severe macular oedema; previous or present history of malignant disease, other than basal cell carcinoma and cervical carcinoma in situ, within the past 5 years; previous malignant disease with relapse or therapy within the past 5 years; previous treatment with systemic growth angiogenic factors or with stem cell therapy; women pregnant or breastfeeding, or of childbearing potential not protected by an effective contraceptive method of birth control; men not following effective contraceptive method with their partner of childbearing potential during the study
Interventions	Treatment: NV1FGF, 0.2 mg/mL, eight 0.5‐mg intramuscular injections in the index leg (affected leg; if disease affected both legs and both were unsuitable for revascularisation, the leg with the lowest ABI or TBI), 4 injections into the calf (anterior and posterior regions) and 4 into the thigh on days 1, 15, 29, and 43; injection sites selected according to an accessible good striated muscle mass and as close as possible to areas of known collateral blood flow development Control: placebo, given in the same manner as treatment
Outcomes	Follow‐up times: 2, 4, and 6 weeks and 2, 6, 9, and 12 months (exploratory extended safety assessment at 18, 24, 30, and 36 months) Outcomes: Amputation, Death, Skin lesion status, Pain intensity at rest (VAS), Functionality and general health assessment ‐ ambulatory function and residential status for patients (Deneuville questionnaire) and overall QoL (using EuroQoL), Admittance to hospital for amputation and other CLI‐related issues; ABI; TBI; safety assessment (adverse events, subjective symptoms, vital signs, ECG, ophthalmic exam, blood tests)
Notes	Study period: recruitment from 1 December 2007 to 31 July 2009 NCT00566657
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Used a central interactive voice response system by block size of 4 and stratified by diabetes status and country; "generated by an electronic technique"; randomised 1:1
Allocation concealment (selection bias)	Low risk	Used a central interactive voice response system for randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Visually identical matching placebo; "Investigators, patients and study teams were masked to treatment"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Investigators, patients and study teams were masked to treatment"
Incomplete outcome data (attrition bias) All outcomes	Low risk	No participants were lost to follow‐up and all discontinued clearly reported; ITT analysis performed
Selective reporting (reporting bias)	Unclear risk	Did not report ABI/TBI; pain severity by VAS; QoL outcomes, which were indicated in the Methods; the additional publication ‐ Van Belle 2011 ‐ does mention baseline geographical and diabetes status but does not provide the data in a meaningful way
Other bias	Unclear risk	Funded by Sanofi‐Aventis; the sponsor was responsible for data monitoring, data collection, and data analysis but had no role in data interpretation or writing of the report