Panes 2016.

Study characteristics
Methods	Multicentre phase III, placebo‐control randomised trial of two parallel groups (conducted in 49 hospitals in seven European countries and Israel).
Participants	212 participants were included from July 6, 2012 to July 27, 2015. Inclusion of adult participants (≥18 years) with Crohn's disease and treatment refractory draining complex perianal fistula. Inclusion criteria: "Enrolled patients had non‐active or mildly active luminal Crohn’s disease for at least 6 months, defined by a Crohn’s Disease Activity Index (CDAI) of 220 or less and had complex perianal fistulas, defined as one or more of the following: high intersphincteric, high trans‐sphincteric, extra‐sphincteric, or supra‐sphincteric origin; at least two external openings; or associated collections. The fistulas had to have a maximum of two internal and three external openings, and had to have been draining for at least 6 weeks before inclusion." "Eligible patients had to be refractory to at least one of the following treatments: the antibiotics ciprofloxacin or metronidazole (refractory defined as no response after 1 month), the immunomodulators azathioprine, 6‐mercapto purine, or methotrexate (refractory defined as no response after 3 months), or induction or maintenance anti‐TNF treatments."
Interventions	212 Participants were randomly assigned (1:1) using a pre‐established randomisation list. Intervention group: 107 participants were assigned to allogeneic, expanded, adipose‐derived stem cells (Cx601) single intralesional injection of 120 million (5million cells/ml) single injection Cx601 cells. Cells were provided from Human lipoaspirates from donor liposuction (AT) Control group: 105 participants were assigned to placebo 24 mL saline solution.
Outcomes	The primary endpoint was combined remission at week 24 (i.e. clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI. There were later published data of the follow‐up of patients for longer periods of time.
Notes	Trial start date: July 6, 2012 Trial ending date: July 27, 2015 Trial registry number: NCT01541579 Funding Sourse: Sponsor: Tigenix S.A.U. Information provided by: Takeda ( Tigenix S.A.U. ) Conflict of interest: JP has received personal fees from TiGenix, AbbVie, Boehringer Ingelheim, Galapagos, Pfi zer, Janssen, and Takeda. DG‐O has received personal fees from TiGenix, and has a patent “Identifi cation and isolation of multipotentcells from non‐osteochondral mesenchymal tissue” (10157355957US), pending to TiGenix, and a patent “Use of adipose tissue‐derived stromal stem cells in treating fi stula” (US11/167061), pending to TiGenix. GVA has received personal fees from TiGenix, MSD, Janssen, and Takeda; and grants and personal fees from AbbVie. JFC has received grants and personal fees from AbbVie, Janssen, and Takeda; personal fees from Amgen, Boehringer Ingelheim, Celgene, Celltrion, Enterome, Ferring, Genentech, Medimmune, Merck, Pfizer, Protagonist, Second Genome, Seres, Shire, Theradiag, and PPM Services; and stock options from Genfit and Intestinal Biotech Development. WR has received personal fees from TiGenix; has served as a speaker for Abbott Laboratories, AbbVie, Aesca, Aptalis, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, Schering‐Plough, Shire, Takeda, Therakos, Vifor, and Yakult; has served as a consultant for Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, BioClinica, Biogen IDEC, Boehringer Ingelheim, Bristol‐Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, Elan, Falk Pharma, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestlé, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Schering‐Plough, Second Genome, Setpointmedical, Takeda, Therakos, TiGenix, UCB, Vifor, Zyngenia, and 4SC; has served as an advisory board member for Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas,AstraZeneca, Avaxia, Biogen IDEC, Boehringer Ingelheim, Bristol‐Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestlé, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Schering‐Plough, Second Genome, Setpointmedical, Takeda, Therakos, TiGenix, UCB, Zyngenia, and 4SC; and has received research funding from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma, Immundiagnsotik, and MSD. DCB reports unrestricted research grants from Shire and Hitachi; personal fees and non‐financial support from AbbVie, Merck (MSD), Takeda, Ferring, Recordati, Genentech (Roche Group), Janssen, and Dr Falk; personal fees from Biogen, Foreward Pharma, and Tigenix; and non‐financial support from Nestlé. All of his activities and contracts conform with the “FSA‐Kodex Fachkreise” (voluntary selfmonitoring code for expert consultants to the pharmaceutical industry), have been checked by the legal department of Charité Universitätsmedizin Berlin, and have been approved by the directorate of the Faculty of Medicine Charité Universitätsmedizin Berlin. AD has received grants and non‐financial support from TiGenix; and personal fees and non‐financial support from AbbVie, Dr Falk, Ferring, MSD, Takeda, Pharmacosmos, Mundipharma, Vifor, Hospira, Hexal, Allergosan, Janssen, Otsuka, and TiGenix. MN has received personal fees and non‐financial support from AbbVie, MSD, and Takeda; and personal fees from Boehringer Ingelheim. MF has received non‐financial support from TiGenix; grants, personal fees, and non‐financial support from Takeda; and personal fees and non‐financial support from MSD, Janssen, AbbVie, Chiesi, Tillotts, Ferring, Falk, Mitsubishi, Zeria, and Boehringer Ingelheim. LK‐S has received non‐financial support from and been a principal investigator for a study sponsored by TiGenix; has been a principal investigator for a study sponsored by SigmaTau and Sanofi ; has received personal fees from MSD, AbbVie, Ferring, MerckSerono/Dr Falk, Chiesi, Novartis, Roche, Abbott, and Phadia Austria/Thermo Fisher Scientifi c; and has received non‐financial support from Mylan, Abbott, MSD, Gilead, MerckSerono/Dr Falk, and Novartis. MPR and AL have received personal fees from TiGenix. SD has received personal fees from AbbVie, MSD, Takeda, Janssen, Mundipharma, Hospira, and Pfizer. JCG, FdlP, and EG declare no competing interests.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomly assigned (1:1) by a centrally located computer‐generated randomisation list."
Allocation concealment (selection bias)	Low risk	"centrally located computer‐generated randomisation list" "Treatments were assigned using a pre‐established randomisation list generated by the Department of Biostatistics, Linical (Madrid, Spain)."
Blinding of participants and personnel (performance bias) All outcomes	High risk	"Masking of treatments was not possible because the cell suspension was clearly different to saline solution (i.e., placebo)."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"a masked gastroenterologist and radiologist both assessing the therapeutic effect." "radiologists who centrally read MRI scans were provided with figures to identify the treated fistulas, but were masked to patient data, order of examinations, and treatment received. Surgeons were not permitted to share information about the treatment used in the surgical procedure with the gastroenterologist and were not allowed to participate in any clinical assessment of the fistula during the study."
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was done Reasons for withdrawal in both groups were clearly mentioned
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes match those in protocol.
Other bias	Low risk	No differenecs in baseline characteristics