Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischaemia

Bobak Moazzami; Zinat Mohammadpour; Zohyra E Zabala; Ermia Farokhi; Aria Roohi; Elena Dolmatova; Kasra Moazzami

doi:10.1002/14651858.CD008347.pub4

Trasplante intramuscular local de células mononucleares autólogas de médula ósea para la isquemia crítica de los miembros inferiores

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NCT00753025. Autologous bone marrow for lower extremity ischemia treating. clinicaltrials.gov/ct2/show/study/NCT00753025 (first received 16 September 2008).

NCT01446055. Safety and efficacy study of autologous BM-MNC processed by two methods for treating patients with chronic limb ischemia. clinicaltrials.gov/ct2/show/study/NCT01446055 (first received 4 October 2011).

NCT02454231. Monocentric trial: stem cell emergency life threatening limbs arteriopathy (SCELTA). clinicaltrials.gov/ct2/show/NCT02454231 (first received 27 May 2015).

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Referencias de otras versiones publicadas de esta revisión

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otras referencias

Moazzami K, Majdzadeh R, Nedjat S. Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia. Cochrane Database of Systematic Reviews 2011, Issue 12. Art. No: CD008347. [DOI: 10.1002/14651858.CD008347.pub2]

Moazzami K, Moazzami B, Roohi A, Nedjat S, Dolmatova E. Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No: CD008347. [DOI: 10.1002/14651858.CD008347.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Barc 2006

*Study characteristics*
Methods	Study design: stated as randomised Method of randomisation: not stated Blinding: not stated Exclusions postrandomisation: not stated Losses to follow‐up: not stated
Participants	Country: Poland Participants: 29 randomised Mean age: not stated Sex: not stated Inclusion criteria: patients with CLI with risk of amputation presence of rest pain and/or necrosis lasting > 12 weeks no progress after 8 weeks of conventional therapy ABI < 0.5 in 2 independent examinations performed during the 7‐day interval pre‐inclusion peripheral type of atherosclerosis and no possibility for operative therapy, confirmed in angiogram Exclusion criteria: age < 18 years need for urgent amputation reasons for ischaemia other than atherosclerosis cancer absence of conscious consent lack of understanding of the idea of the therapy by patient poor general condition (life expectancy < 6 months)
Interventions	Treatment group: type of cells: BMMNC cell isolation: not mentioned dose of cells: not reported route and frequency of delivery: multiple IM injections Control group: not stated in the paper, but described by the authors as standard conservative therapy
Outcomes	Primary outcomes: ABI photographic documentation of ischaemic ulcerations and necrosis subjective parameters (feeling of pain in VAS, QoL in WHO scale) Secondary outcomes: not stated Outcome assessment points: baseline and months 1, 3, and 6
Funding	Not reported
Declarations of interest	Not reported
Notes	It is unclear who injects monocytes.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The study is described as randomised, but details are unclear.
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not mentioned
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All participants are accounted for.
Selective reporting (reporting bias)	High risk	The ABI and pain data were not reported in sufficient detail to include in the analysis.
Other bias	Low risk	We did not identify any other potential sources of bias.

Li 2013

*Study characteristics*
Methods	Study design: stated as randomised Method of randomisation: not stated Blinding: single‐blind Exclusions postrandomisation: stated that 16 patients could not be evaluated for haemodynamic assessment because of extensive ulceration that made ankle pressure assessment not feasible Losses to follow‐up: not stated
Participants	Country: China Participants: 58 randomised Mean age: 61 years in treatment group, 63 years in control group Sex: male and female Inclusion criteria: evidence of CLI including rest pain and/or non‐healing ischaemic ulcers for a minimum of 4 weeks without improvement in response to conventional therapies Exclusion criteria: history of malignancy evidence of possible malignancies after evaluation with carcinoembryonic antigen levels, chest radiographs, CT scans, and mammography in women or prostate examination in men
Interventions	Treatment group: type of cells: BMMNC cell isolation: cells were extracted from the posterior superior iliac spine. BMMNCs were isolated from the bone marrow by density gradient centrifugation with lymphocyte separating fluid. Cell counting was performed. Isolated BMMNCs were diluted into 50 to 120 mL suspensions to be transplanted. dose of cells: 1 × 10⁷ piece [sic]/mL BMMNC transplant route and frequency of delivery: multiple IM injections Control group: 0.9% sodium chloride (saline)
Outcomes	Primary outcomes: safety assessments included adverse events, physical examination, cancer screening, ECG, blood chemistry, haematology, and urinalysis for fever, allergies, myocardial, stoke, malignancy, and death Secondary outcomes: haemodynamic improvement (an absolute increase of > 15% in the ABI) skin ulcers improvement using photographic documentation of ischaemic ulcerations pain score improvement using VAS limb survival Outcome assessment points: baseline and months 1, 3, and 6
Funding	Not reported
Declarations of interest	Not reported
Notes	It is unclear who injects monocytes.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The study is described as randomised, but details are unclear.
Allocation concealment (selection bias)	Unclear risk	There was no information regarding allocation.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "This was a single blinded study aimed at analyzing the effect of..." Comment: not stated who was blinded
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "This was a single blinded study aimed at analyzing the effect of..." Comment: not stated who was blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "Sixteen patients could not be evaluated for hemodynamic assessment because of extensive ulceration that made ankle pressure assessment not feasible" and "Fifteen patients were not evaluated for pain scores owing to minor surgical intervention just before the transplant or they could not understand the VAS scale"
Selective reporting (reporting bias)	Low risk	We did not identify any reporting bias.
Other bias	Low risk	We did not identify any other potential sources of bias.

Lindeman 2018

*Study characteristics*
Methods	Study design: stated as randomised Method of randomisation: computer‐generated randomisations and allocation Blinding: fully blinded Exclusions postrandomisation: not stated Losses to follow‐up: 1 participant in the placebo group
Participants	Country: the Netherlands Participants: 54 randomised Mean age: 58.5 years in treatment group, 57.8 years in control group Sex: male and female Inclusion criteria: persistent disabling claudication (Fontaine’s stages IIb/III or Rutherford’s categories 3/4) or CLI (Fontaine’s stages IV or Rutherford’s categories 5/6) despite > 6 months optimal medical therapy (including exercise therapy, and revascularisation attempts in accordance with prevailing guidelines) Exclusion criteria: diabetes immune suppressive therapy age < 18 years compromised life expectancy (anticipated survival < 1 year) severe tissue loss or non‐manageable pain with an anticipated need for amputation within the first month of therapy
Interventions	Treatment group: type of cells: BMMNC cell isolation: BMMNCs were collected from multiple locations from the posterior iliac crests. The obtained bone marrow suspension was then filtered and concentrated to a final volume of 40 mL on the COBE Spectra Apheresis System (Gambro, Stockholm, Sweden) in the LUMC GMP‐facility without any further treatment. dose of cells: 1.7 × 10⁹ total route and frequency of delivery: IM injections in 40 locations (1 mL per injection site) Control group: diluted autologous peripheral blood, which was visually indistinguishable from the BMMNC
Outcomes	Primary outcomes: PFWD or limb salvage full wound recovery Secondary outcomes: ABI SF‐36 Pain (BPI‐SF) Time points for assessment: months 1, 6, and 12
Funding	Not reported
Declarations of interest	Not reported
Notes	It is unclear who injects monocytes.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer randomization and allocation were done after bone marrow collection, by the stem laboratory in permuted blocks of size 4 in 2 strata (disabling claudication or CLI) and secured until all data entry was completed and the database was locked"
Allocation concealment (selection bias)	Low risk	Allocation was adequately concealed.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "All patients, clinicians, and trial investigators remained blinded for the treatment allocation until reaching the secondary 12 month end point."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All patients, clinicians, and trial investigators remained blinded for the treatment allocation until reaching the secondary 12 month end point."
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants were analysed, except for 1 participant in the placebo group. Quote: "One patient in the placebo group was unable to comply with the follow‐up (language barrier), hence 25 patients could be evaluated."
Selective reporting (reporting bias)	Low risk	The clinical measures prespecified in the protocols were adequately reported in the results.
Other bias	Low risk	None suspected.

Pignon 2017

*Study characteristics*
Methods	Study design: stated as randomised Method of randomisation: website‐generated randomisation Blinding: double‐blind Exclusions postrandomisation: not stated Intention‐to‐treat analysis: used Losses to follow‐up: 1 participant in placebo group and 1 participant in treatment group
Participants	Country: France Participants: 38 randomised Mean age: 72 years in treatment group, 65 years in control group Sex: male and female Inclusion criteria: age ≥ 18 years presented with atherosclerosis‐related CLI with no sign of improvement following previous appropriate medical treatment Exclusion criteria: Buerger’s disease active infection uncontrolled diabetes mellitus prior history of neoplasm or malignancy contraindication for general anaesthesia prothrombin time < 50% myocardial or brain infarction within 3 months any medical condition contraindicating the initiation of anticoagulation unexplained haematological abnormality HIV hepatitis B or C virus infection any concomitant disease associated with a life expectancy of < 1 year
Interventions	Treatment group: type of cells: BMMNC cell isolation: 500 mL of bone marrow collected from the posterior iliac crests. 8 centres used a blood‐cell separator (COBE Spectra, version 4, Bone Marrow Processing Program, Gambro BCT, Lakewood, CO, USA); 2 centres used a blood‐cell separator requiring a Ficoll density‐gradient for isolation of the BMMNC. dose of cells: 1.3 × 10⁹ total (not clear in report) route and frequency of delivery: IM injections (30 intramuscular injections of 1 mL) Control group: 30 mL saline with 4 mL autologous peripheral blood
Outcomes	Primary outcomes: major amputation rate mortality Secondary outcomes: ABI TcPO₂ ulcers pain Time points for assessment: baseline, days 1, 3, 15, 28, and then months 6 and 12
Funding	The reported work was supported by the French Ministry of Health (Programme Hospitalier de Recherche Clinique 2007) and by the French Blood Agency.
Declarations of interest	Not reported
Notes	It is unclear who injects monocytes.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed by the local investigator in charge of the patient, through a dedicated website, with stratification by center."
Allocation concealment (selection bias)	Low risk	Allocation was adequately concealed.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The steering committee, the investigators, the observers, and the patients were unaware of the treatment allocation."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The steering committee, the investigators, the observers, and the patients were unaware of the treatment allocation."
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 participants (1 in placebo group and 1 in treatment group) dropped out of study due to adverse events. Quote: "Therefore, the modified ITT analysis excluded these 2 patients and the analysis was conducted on 19 patients in the placebo group and 17 in the BMMNC group."
Selective reporting (reporting bias)	High risk	The data for ABI and pain were not reported in sufficient detail to include in the analysis.
Other bias	Low risk	None suspected.

ABI: ankle‐brachial index
BMMNC: bone marrow mononuclear cell
BPI‐SF: Brief Pain Inventory‐Short Form
CLI: critical limb ischaemia
CT: computed tomography
ECG: echocardiographs
IM: intramuscular
PFWD: pain‐free walking distance
QoL: quality of life
SF‐36: 36‐Item Short‐Form Health Survey
TcPO₂: transcutaneous pressure of oxygen
VAS: visual analogue scale
VEGF: vascular endothelial growth factor
WHO: World Health Organization

Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Benoit 2011	This study used bone marrow from the iliac crest, but after aspiration, BMMNC was processed into 40 mL of concentrate using the SmartPReP2 Bone Marrow Aspirate Concentrate (BMAC) system.
BONMOT 2008	The study is an ongoing RCT investigating the effects of autologous bone marrow concentrate, not BMMNCs.
Burt 2010	This study assessed the safety and feasibility of autologous CD133+ cells and included no control group.
Capiod 2009	The study compared the effect of transplantation of BMMNCs or G‐CSF‐mobilised PBMNCs, and included no control group.
Chen 2009	The study included people with diabetic foot not CLI, and participants received autologous bone marrow MSC, not mononuclear cells.
Debin 2008	The study investigated the effects of bone marrow MSC, not BMMNCs.
Dong 2013	The study investigated the effects of purified CD34+ cells, not BMMNCs.
Dong 2018	The study compared the effect of transplantation of PBMNCs or purified CD34+ cells, and included no control group.
Du 2017	The study assessed the clinical efficacy of implanted umbilical cord MSCs combined with bone marrow stem cells compared with implanted bone marrow stem cells for treatment of lower limb ischaemia.
Flugelman 2017	The study assessed venous endothelial cells combined with venous smooth muscle cells.
Frogel 2017	This is a pilot open‐label study of treatment progenitor cells derived from peripheral blood for people with CLI.
Gupta 2013	The study investigated the effects of allogeneic bone marrow‐derived MSC, not BMMNC.
Gurunathan 2009	The study is an ongoing RCT investigating the effects of autologous bone marrow concentrate, not BMMNCs.
Higashi 2010	The study investigated the combined effect of BMMNC implantation and sarpogrelate, a selective 5‐HT(2A) antagonist.
Holzinger 1994	The study investigated people with chronic skin ulcers caused by chronic arterial occlusive disease or venous post‐thrombotic syndrome, not CLI.
Horie 2018	This RCT evaluated the efficacy and safety of G‐CSF‐mobilised PBMNC transplantation in people with PAD.
Huang 2005a	The study investigated PBMNC, not BMMNC.
Iafrati 2011	The study investigated BMA concentrate, not BMMNC.
Iafrati 2016	The study investigated BMA concentrate, not BMMNC.
JUVENTAS 2008	The study is an ongoing RCT investigating the effects of IA injection of BMMNCs.
Kirana 2007	The study investigated people with diabetic foot ulcers, not CLI.
Kirana 2012	The study investigated people with diabetic foot ulcers, not CLI.
Klepanec 2012	The study compared IA and IM MSC therapy with no control group.
Korymasov 2009	The study is a randomised triple‐arm study investigating the safety and effectiveness of highly purified CD133+ autologous stem cells in CLI.
Lasala 2011	The study investigated the transplantation of an autologous bone marrow‐derived combination stem cell product.
Lu 2011	The study compared bone marrow MSC with BMMNCs with no control group.
Madaric 2011	The study compared IA and IM application of autologous BMC transplantation.
Majumdar 2015	This phase 2 study assessed allogeneic MSC in CLI.
Mohamed 2020	The study included bone marrow mesenchymal stromal cell therapy.
Molavi 2016	This RCT investigated the safety and efficacy of repeated BMMNC injections in comparison with a single BMMNC injection in CLI patients.
Murphy 2017	This double‐blinded, placebo‐controlled trial assessed the safety and efficacy of autologous concentrated BMA versus placebo.
NCT00282646	This is an ongoing RCT investigating the effects of IA injection of autologous BMMNCs versus placebo.
NCT00306085	The study investigated patients with peripheral atherosclerosis, not CLI.
NCT00498069	This is an ongoing RCT investigating the effects of BMCs, not BMMNCs.
NCT00539266	This is an ongoing RCT investigating the effects of BMCs, not BMMNCs.
NCT00595257	This is an ongoing RCT investigating the effects of autologous bone marrow concentrate, not BMMNCs.
NCT00616980	This is an ongoing RCT investigating the effects of peripheral blood‐derived stem cells, not BMMNCs.
NCT00913900	The study is an ongoing RCT investigating the effects of adult stem cells.
NCT00922389	This is an ongoing RCT investigating the effects of CD34 positive cells, not BMMNCs.
NCT00955669	This is an ongoing RCT comparing autologous MSC and mononuclear cells, not BMMNCs.
NCT01049919	This is an ongoing RCT investigating the effects of autologous concentrated BMA, not BMMNCs.
NCT01245335	This is an ongoing RCT investigating the effects of BMA concentrate, not BMMNCs.
NCT01584986	This RCT assessed the safety and efficacy of autologous ACPs compared with SMT.
NCT02336646	This RCT compared allogeneic MSCs versus placebo in people with CLI.
NCT03174522	This clinical trial compared Rexmyelocel‐T versus placebo in people with CLI.
NCT03214887	This clinical trial investigated the safety and efficacy of hyaluronan combined with BMMNCs for PAD.
NCT03304821	This double‐blind, placebo‐controlled RCT examined whether 3 weeks of 3‐times‐a week injection of GM‐CSF would improve measures of ischaemia in people with IC compared with placebo.
NCT03339973	This clinical trial is investigating the efficacy and safety of 1 dose of allo‐APZ2‐PAOD administered IM into the affected lower leg of people with PAD.
Niven 2017	This pilot open‐label study examined treatment with progenitor cells for PAD.
Ohtake 2017	This prospective phase 1/2 interventional clinical trial examined autologous G‐CSF‐mobilised CD34+ cell transplantation in haemodialysis patients with CLI.
Pawan 2012	The study investigated adult bone marrow‐derived allogeneic MSC.
Perin 2011	The study investigated autologous therapy with bone marrow‐derived aldehyde dehydrogenase bright cells. These cells are derived from CD15 and glycophorin A‐expressing cells from autologous bone marrow via immunomagnetic beads and cell sorters.
Perin 2017	The study investigated autologous therapy with bone marrow‐derived aldehyde dehydrogenase bright cells. These cells are derived from CD15 and glycophorin A‐expressing cells from autologous bone marrow via immunomagnetic beads and cell sorters.
Poole 2013	This trial investigated the effects of GM‐CSF, not cell therapy, in people with IC.
Prochazka 2010	This RCT investigated major limb amputation in participants given autologous BMC compared to those given standard care for CLI and foot ulcer.
PROVASA 2011	This is a multicentre, phase II, double‐blind RCT comparing IA administration of BMMNC or placebo followed by active treatment with BMMNC (open‐label) after 3 months.
RESTORE‐CLI 2012	This is an ongoing RCT investigating the effects of vascular repair cells, not BMMNCs.
Sharma 2021	In this study, BMMNC was injected IA, not IM.
Skóra 2015	This study investigated autologous BMMNC plus VEGF, not BMMNC alone.
Subramaniyam 2009	The study investigated patients with IC, not CLI.
Szabo 2013	The study investigated the effects of autologous stem cell therapy, not BMMNCs.
Teraa 2015	This double‐blind, placebo‐controlled RCT compared BMMNCs versus placebo in people with limb ischaemia, which was administered IA.
Tournois 2015	This phase 1 and 2 clinical trial examined BMC therapy products and cell therapy products obtained by cytapheresis (peripheral blood‐cell therapy products).
Walter 2011	The study compared the effect of IA route of transplantation.
Wang 2014	This trial assessed the efficacy and safety of the combination of peripheral blood mononuclear cells and Panax notoginseng saponins for treatment of CLI.
Wang 2017	This multicentre, double‐blind, placebo‐controlled RCT assessed the efficacy of IM injections of concentrated BMA for promoting amputation‐free survival in people with poor‐option CLI.
Wang 2018	This study compared IM injections of allogeneic MSCs or autogenous concentrated BMA.
Wijnand 2018	This study used allogeneic MSC for CLI.
Zafarghandi 2010	The study compared the effect of transplantation of BMMNCs with G‐CSF‐mobilised PBMNCs and included no control group.
Zhang 2010	The study only included people with diabetes.
Zhao 2008	The study investigated the effect of combined PBMNCs and BMMNCs injection versus placebo.
Zhou 2017a	This open, parallel‐control RCT compared BMMNC with SMT.
Zhou 2017b	This prospective, single‐centre, open‐label RCT compared peripheral blood CD34+ cells transfected with VEGF‐165 versus SMT.

ACPs: angiogenic cell precursors
BMA: bone marrow aspirate
BMC: bone marrow cell
BMMNC: bone marrow mononuclear cell
CLI: critical limb ischaemia
G‐CSF: granulocyte colony‐stimulating factor
GM‐CSF: granulocyte‐macrophage colony‐stimulating factor
IA: intra‐arterial
IC: intermittent claudication
IM: intramuscular
MSC: mesenchymal stem cells
PAD: peripheral arterial disease
PBMNC: peripheral blood‐derived mononuclear cell
RCT: randomised controlled trial
SMT: standard medical treatment
VEGF: vascular endothelial growth factor

Characteristics of ongoing studies [ordered by study ID]

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NCT00753025

Study name	Autologous bone marrow for lower extremity ischaemia treating
Methods	Allocation: randomised Endpoint classification: safety/efficacy study Intervention model: parallel assignment Masking: quadruple (participant, care provider, investigator, outcomes assessor) Primary purpose: treatment
Participants	Inclusion criteria: obliterating lower extremity atherosclerosis IIB stage (on Fontaine classification) PFWD of 10 to 50 m pulse absence on dorsalis pedis, tibialis posterior, poplitea absence of ischaemia in rest and necrotic changes mainly distal form of disease (lesion of a superficial femoral artery, a popliteal artery, anticnemion (anterior edge of the tibia) arteries) according to an angiography that testifies to impossibility of reconstructive operation performance after lumbar sympathectomy and tibial bone osteoperforations executed previously heavy smokers Exclusion criteria: insulin‐dependent diabetes myocardial infarction or stroke within the past year idiopathic hypertension III stage anaemia and other diseases of blood decompensation of chronic diseases that are contraindications to any surgical operation HIV infection A virus hepatitis oncological disease prior history of chemotherapy
Interventions	Biological: injection of isolated CD133+ cells
Outcomes	Primary outcome measure: increase in PFWD
Starting date	September 2008
Contact information	Andrey Toropovskiy, Clinical Center of Cellular Technologies, Russia
Notes	Primary completion date: September 2008

NCT01446055

Study name	Safety and efficacy study of autologous BMMNC processed by two methods for treating patients with CLI
Methods	Allocation: randomised Endpoint classification: safety/efficacy study Intervention model: parallel assignment Masking: single‐blind (participant) Primary purpose: treatment
Participants	Inclusion criteria: Fontaine stage 2 to 4 or resting ABI < 0.7 age between 20 and 80 years signed informed consent, voluntary participants diagnosis of lower extremity arterial occlusive disease, or diabetic lower limb ischaemia, or Buerger’s disease Exclusion criteria: poorly controlled diabetes (glycated haemoglobin > 7.0%) and proliferative retinopathy (III to IV stage) malignancy history in the past 5 years or serum level of tumour markers elevated more than doubled severe heart, liver, kidney, respiratory failure or poor general condition and cannot tolerate BMMNC implantation serious infections (such as cellulitis, osteomyelitis, etc.) or gangrene such that a major amputation cannot be avoided aortic or iliac or common femoral artery occlusion pregnant female, or reproductive age female, who wants to give birth throughout the course of the study life expectancy less than 1 year
Interventions	Experimental: autologous BMMNC is enriched with ResQ process (an automatic cell separator). Then the cell product is implanted into the ischaemic limbs of a participant. Active comparator: a conventional method based on Ficoll cell separation is used to process bone marrow
Outcomes	Primary outcomes: cell treatment‐related adverse event: temperature, pulse, respiration, blood pressure, routine analysis of blood and urine, liver function (ALT, AST), renal function (blood urea nitrogen, creatinine), function of coagulation (APTT, prothrombin time, fibrinogen, thrombin time), ECG, local inflammatory response, cell treatment‐related death, cell treatment‐related unexpected amputation Secondary outcomes: ulcer size rest pain score cold sensation score claudication distance (m) resting ABI resting TcO (mmHg) collateral vessel score amputation rate skin microcirculation measurement resting TBI
Starting date	October 2011
Contact information	Contact: Yongquan Gu, MD, Xuanwu Hospital, Beijing; gu‐[email protected]
Notes	The recruitment status of this study is unknown because the information has not been verified recently on ClinicalTrials.gov.

NCT02454231

Study name	Monocentric trial: stem cell emergency life threatening limbs arteriopathy (SCELTA)
Methods	Allocation: randomised Endpoint classification: safety/efficacy study Intervention model: parallel assignment Masking: open‐label Primary purpose: treatment
Participants	Inclusion criteria: men and women older than 40 years of age with a diagnosis of CLI due to atherosclerosis of the lower extremities, as defined by the presence of persistent rest pain requiring systemic and continued analgesic treatment in the past 15 days and/or the presence of trophic lesions imputable to the occluding arteriopathy, ABI < 0.40 (with systolic ankle pressure < 50 to 70 mmHg), TBI < 0.40 (with big toe systolic pressure < 30 to 50 mmHg), and TcO < 30 mmHg eligible for treatment and enrolled only after demonstration that intravascular or surgical revascularisation was not possible, as revealed by echography and angio‐CAT, or when the patient refused to undergo surgical treatments and after written informed consent was obtained Exclusion criteria: age < 40 not atherosclerotic CLI myocardial infarction occurrence within 6 months cardiac failure of III‐IV class NYHA ejection fraction < 40% arterial hypertension (> 160/100 mmHg) uncontrolled despite usage of 2 antihypertensive drugs presence of current or chronic severe infectious disease osteomyelitis diabetes with glycated haemoglobin > 7.5 proliferative diabetic retinopathy haemorrhagic disorders non‐atherosclerotic arteriopathy chronic airway insufficiency (pO₂ < 65 mmHg, pCO₂ > 0.50 mmHg) renal failure (creatinine > 2 mg/dL) contraindications or intolerance to contrast media for radiological imaging
Interventions	Experimental: peripheral blood EPC injection Active comparator: BMMNC injection
Outcomes	Primary outcomes: safety as measured by evaluation of any adverse event temporarily correlated with treatment changes in ischaemic leg perfusion from baseline Secondary outcomes: improvement in mean values of TcO improvement in mean values of ABI improvement in vessel anatomical status improvement in leg perfusion improvement in vessel anatomical status quality of life improvement improvement in rest pain improvement in trophic limb lesions reduction in number of major amputations improvement in microvascular anatomy
Starting date	September 2009
Contact information	Contacts: Enrico Maggi, professor, University of Florence, Italy; [email protected] Francesco Annunziato, professor; [email protected]
Notes	Primary completion date: May 2015

ABI: ankle‐brachial index
Angio‐CAT: computerised tomography (CT) coronary angiogram
APTT: activated partial thromboplastin time
ALT: alanine aminotransferase
AST: aspartate aminotransferase
BMI: body mass index
BMMNC: bone marrow mononuclear cells
CLI: critical limb ischaemia
DVT: deep vein thrombosis
ECG: electrocardiography
EPC: endothelial progenitor cells
G‐CSF: granulocyte colony‐stimulating factor
IC: intermittent claudication
IM: intramuscular
NYHA: New York Heart Association
PAD: peripheral arterial disease
pCO₂: partial pressure of carbon dioxide
PB‐MNC: peripheral blood mononuclear cells
PFWD: pain‐free walking distance
pO₂: partial pressure of oxygen
TASC: TransAtlantic Intersociety Consensus
TBI: toe brachial index
TcO: transcutaneous oxygen pressure

Data and analyses

Open in table viewer

Comparison 1. BMMNC versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause mortality Show forest plot	3	123	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.15, 6.63]
Open in figure viewer Analysis 1.1 Comparison 1: BMMNC versus control, Outcome 1: All‐cause mortality
1.2 Amputation Show forest plot	4	176	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.27, 0.99]
Open in figure viewer Analysis 1.2 Comparison 1: BMMNC versus control, Outcome 2: Amputation
1.3 Amputation ‐ sensitivity analysis Show forest plot	2	89	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.19, 1.39]
Open in figure viewer Analysis 1.3 Comparison 1: BMMNC versus control, Outcome 3: Amputation ‐ sensitivity analysis
1.4 Side effects and complications Show forest plot	4	176	Risk Ratio (M‐H, Random, 95% CI)	2.13 [0.50, 8.97]
Open in figure viewer Analysis 1.4 Comparison 1: BMMNC versus control, Outcome 4: Side effects and complications
1.5 Side effects and complications ‐ sensitivity analysis Show forest plot	2	89	Risk Ratio (M‐H, Random, 95% CI)	2.69 [0.11, 63.18]
Open in figure viewer Analysis 1.5 Comparison 1: BMMNC versus control, Outcome 5: Side effects and complications ‐ sensitivity analysis

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1: BMMNC versus control, Outcome 1: All‐cause mortality

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Analysis 1.2

Comparison 1: BMMNC versus control, Outcome 2: Amputation

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Analysis 1.3

Comparison 1: BMMNC versus control, Outcome 3: Amputation ‐ sensitivity analysis

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Analysis 1.4

Comparison 1: BMMNC versus control, Outcome 4: Side effects and complications

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Analysis 1.5

Comparison 1: BMMNC versus control, Outcome 5: Side effects and complications ‐ sensitivity analysis

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Summary of findings 1. Intramuscular injection of bone marrow mononuclear cells (BMMNC) compared to control for treatment of critical lower limb ischaemia (CLI)

Outcomes	Anticipated absolute effects (95% CI)^*		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Intramuscular injection of bone marrow mononuclear cells (BMMNC) compared to control for treatment of critical lower limb ischaemia (CLI)
Patient or population: people with CLI who were not suitable for revascularisation and showed no improvement in response to the best standard therapy Setting: hospital Intervention: BMMNC^a Comparison: control^b
Outcomes	Risk with control	Risk with BMMNC	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
All‐cause mortality (follow‐up: 6 or 12 months)	Study population		RR 1.00 (0.15 to 6.63)	123 (3 RCTs)	⊕⊝⊝⊝ VERY LOW^c	No deaths were reported for 2 studies (Barc 2006; Pignon 2017). Li 2013 reported 4 deaths (2 in each group) during 6 months follow‐up; these deaths were not considered to be related to treatment. Information regarding mortality was not available in 1 study (Lindeman 2018).
All‐cause mortality (follow‐up: 6 or 12 months)	32 per 1000	32 per 1000 (5 to 210)	RR 1.00 (0.15 to 6.63)	123 (3 RCTs)	⊕⊝⊝⊝ VERY LOW^c
Reduction in pain Various scales including VAS, PISQ; scales ranged from 0 to 4/10/100, where 0 = no pain (follow‐up: 3 to 12 months)	All studies reported on pain, but due to different measurements and incomplete information we were unable to pool the data. See comment			176 (4 RCTs)	⊕⊝⊝⊝ VERY LOW^d	Barc 2006 assessed pain with VAS, where 0 was no pain at all and 10 was the most severe pain experienced. Pain levels decreased in both BMMNC and control groups. Li 2013 assessed pain with VAS, but reported the improvement of pain defined as a > 50% decrease in VAS during study follow‐up. Study authors reported a greater reduction in pain in the BMMNC group (P = 0.045). Lindeman 2018 used the PISQ, and reported that no differences were observed in average pain reduction between BMMNC and control group (P = 0.23). Pignon 2017 assessed pain with VAS, where 0 was no pain at all and 100 was the most severe pain experienced. Study authors reported that no differences in pain reduction were observed between the BMMNC and control group.
Incidence of amputation (follow‐up: 6 or 12 months)	Study population		RR 0.52 (0.27 to 0.99)	176 (4 RCTs)	⊕⊝⊝⊝ VERY LOW^e	All studies reported the incidence of amputation. A possible small benefit was no longer seen after removal of 2 studies at high risk of bias in sensitivity analysis (RR 0.52, 95% CI 0.19 to 1.39; 89 participants, 2 studies) (Barc 2006; Li 2013).
Incidence of amputation (follow‐up: 6 or 12 months)	250 per 1000	130 per 1000 (68 to 248)	RR 0.52 (0.27 to 0.99)	176 (4 RCTs)	⊕⊝⊝⊝ VERY LOW^e
Angiographic analysis	See comment			‐	‐	None of the studies reported angiographic analysis.
Increase in ABI An ABI ratio of 0.9 or less indicates PAD. Values between 0.9 and 1.0 are borderline, and above 1.0 is considered normal (follow‐up: range 1 month to 12 months)	All studies measured ABI, but due to incomplete information we were unable to pool the data. See comment			176 (4 RCTs)	⊕⊝⊝⊝ VERY LOW^f	Barc 2006 reported that ABI did not change from baseline during study follow‐up in both BMMNC and control groups. Li 2013 used an absolute increase of > 15% ABI to quantify haemodynamic improvement. Study authors reported that this was greater in the BMMNC group compared to control (P = 0.002). Lindeman 2018 reported no difference in mean ABI between the BMMNC and control groups after 12 months follow‐up (P = 0.50). Pignon 2017 did not show any changes in median ABI value between groups.
Increase in PFWD (m) (follow‐up: 12 months)	See comment			53 (1 RCT)	⊕⊕⊝⊝ LOW^g	Only Lindeman 2018 reported PFWD, finding no clear difference between groups. The mean PFWD for the treatment and control groups at 12 months follow‐up was 128 ± 71 m vs 160 ± 11 m, P = 0.87.
Side effects and complications (follow‐up: 6 or 12 months)	Study population		RR 2.13 (0.50 to 8.97)	176 (4 RCTs)	⊕⊝⊝⊝ VERY LOW^h	All trials reported adverse events. 2 studies reported that no identifiable treatment‐related adverse events were observed, and that the therapy was well‐tolerated (Barc 2006; Pignon 2017). Li 2013 reported adverse events in both BMMNC and control groups (3 vs 1 fever, 1 vs 0 MI, 0 vs 1 stroke). There were no differences in the incidence of adverse events between groups, and the therapy was well‐tolerated Lindeman 2018 reported that leukaemia occurred in 1 participant during the follow‐up period. It is unclear if this was related to the procedure. After applying the sensitivity analysis by removing 2 studies at high risk of bias (Barc 2006; Li 2013), the significance of the results did not change (RR 2.69, 95% CI 0.11 to 63.18).
	23 per 1000	48 per 1000 (11 to 204)	RR 2.13 (0.50 to 8.97)	176 (4 RCTs)	⊕⊝⊝⊝ VERY LOW^h
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ABI: ankle‐brachial index;BMMNC: bone marrow mononuclear cells; CI: confidence interval; CLI: critical limb ischaemia;MI: myocardial infarction; PAD: peripheral arterial disease; PFWD: pain‐free walking distance;PISQ: pain inventory score questionnaire; RCT: randomised controlled trial; RR: risk ratio; VAS: visual analogue scale
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aThe stem cells used in the included RCTs originate from bone marrow. All four trials used mononuclear cells collected during the harvesting procedure from bone marrow and implanted into affected limbs (Barc 2006; Li 2013; Lindeman 2018; Pignon 2017). ^bThe control arms varied across all included RCTs: conventional therapy (Barc 2006), 0.9% sodium chloride (saline) (Li 2013), diluted autologous peripheral blood (Lindeman 2018), 30 mL saline with 4 mL autologous peripheral blood (Pignon 2017). ^cWe downgraded a total of three levels due to concerns related to risk of bias, imprecision (few participants and events), and inconsistency (wide CIs and clinical heterogeneity). ^dWe downgraded one level for concerns related to risk of bias, one level for imprecision (few participants and events), and one level for inconsistency (heterogeneity due to different control arms). ^eWe downgraded one level for concerns related to risk of bias, one level for imprecision (few participants and events), and one level for inconsistency (heterogeneity due to different control arms). ^fWe downgraded one level for concerns related to risk of bias, one level for imprecision (few participants and events), and one level for inconsistency (wide CIs, and heterogeneity due to different control arms). ^gWe downgraded one level for imprecision (few participants and events) and one level for inconsistency (wide CIs, heterogeneity due to different control arms). ^hWe downgraded one level for concerns related to risk of bias, one level for imprecision (few participants and events), and one level for inconsistency (wide CIs).

Summary of findings 1. Intramuscular injection of bone marrow mononuclear cells (BMMNC) compared to control for treatment of critical lower limb ischaemia (CLI)

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Comparison 1. BMMNC versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause mortality Show forest plot	3	123	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.15, 6.63]

1.2 Amputation Show forest plot	4	176	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.27, 0.99]

1.3 Amputation ‐ sensitivity analysis Show forest plot	2	89	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.19, 1.39]

1.4 Side effects and complications Show forest plot	4	176	Risk Ratio (M‐H, Random, 95% CI)	2.13 [0.50, 8.97]

1.5 Side effects and complications ‐ sensitivity analysis Show forest plot	2	89	Risk Ratio (M‐H, Random, 95% CI)	2.69 [0.11, 63.18]

Comparison 1. BMMNC versus control

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Referencias

Referencias de los estudios incluidos en esta revisión

Barc 2006 {published data only}

Li 2013 {published data only}

Lindeman 2018 {published data only}

Pignon 2017 {published data only}

Referencias de los estudios excluidos de esta revisión

Benoit 2011 {published data only}

BONMOT 2008 {published data only}

Burt 2010 {published data only}

Capiod 2009 {published data only}

Chen 2009 {published data only}

Debin 2008 {published data only}

Dong 2013 {published data only}

Dong 2018 {published data only}

Du 2017 {published data only}

Flugelman 2017 {published data only}

Frogel 2017 {published data only}

Gupta 2013 {published data only}

Gurunathan 2009 {published data only}

Higashi 2010 {published data only}

Holzinger 1994 {published data only}

Horie 2018 {published data only}

Huang 2005a {published data only}

Iafrati 2011 {published data only}

Iafrati 2016 {published data only}

JUVENTAS 2008 {published data only}NCT00371371

Kirana 2007 {published data only}

Kirana 2012 {published data only}

Klepanec 2012 {published data only}

Korymasov 2009 {published data only}

Lasala 2011 {published data only}

Lu 2011 {published data only}

Madaric 2011 {published data only}

Majumdar 2015 {published data only}

Mohamed 2020 {published data only}10.1016/j.jcyt.2020.02.007

Molavi 2016 {published data only}

Murphy 2017 {published data only}

NCT00282646 {published data only}

NCT00306085 {published data only}

NCT00498069 {published data only}

NCT00539266 {published data only}NCT00539266

NCT00595257 {published data only}

NCT00616980 {published data only}NCT00616980

NCT00913900 {published data only}NCT00913900

NCT00922389 {published data only}

NCT00955669 {published data only}

NCT01049919 {published data only}

NCT01245335 {published data only}

NCT01584986 {published data only}

NCT02336646 {published data only}

NCT03174522 {published data only}

NCT03214887 {published data only}

NCT03304821 {published data only}

NCT03339973 {published data only}

Niven 2017 {published data only}

Ohtake 2017 {published data only}

Pawan 2012 {published data only}

Perin 2011 {published data only}

Perin 2017 {published data only}

Poole 2013 {published data only}

Prochazka 2010 {published data only}

PROVASA 2011 {published data only}

RESTORE‐CLI 2012 {published data only}NCT00468000

Sharma 2021 {published data only}

Skóra 2015 {published data only}

Subramaniyam 2009 {published data only}

Szabo 2013 {published data only}

Teraa 2015 {published data only}

Tournois 2015 {published data only}

Walter 2011 {published data only}

Wang 2014 {published data only}

Wang 2017 {published data only}

Wang 2018 {published data only}

Wijnand 2018 {published data only}

Zafarghandi 2010 {published data only}

Zhang 2010 {published data only}

Zhao 2008 {published data only}