Sandrine Lablanche1, Marie-Christine Vantyghem2, Laurence Kessler3, Anne Wojtusciszyn4, Sophie Borot5, Charles Thivolet6, Sophie Girerd7, Domenico Bosco8, Jean-Luc Bosson9, Cyrille Colin10, Rachel Tetaz11, Sophie Logerot12, Julie Kerr-Conte2, Eric Renard4, Alfred Penfornis13, Emmanuel Morelon14, Fanny Buron14, Kristina Skaare9, Gwen Grguric10, Coralie Camillo-Brault10, Harald Egelhofer15, Kanza Benomar2, Lionel Badet16, Thierry Berney8, François Pattou2, Pierre-Yves Benhamou17. 1. Department of Endocrinology, Diabetes, and Nutrition, Grenoble Alpes University, Grenoble, France; Inserm U1055, Laboratory of Fundamental and Applied Bioenergetics Grenoble, Grenoble, France. Electronic address: slablanche@chu-grenoble.fr. 2. Department of Endocrinology, Diabetes, and Nutrition, C Huriez Hospital, Lille University Hospital, Lille, France; Inserm 1190, European Genomic Institute for Diabetes, Lille, France. 3. Hôpitaux Universitaires de Strasbourg, Service d'Endocrinologie Diabète et Maladies Métaboliques, and Equipe d'Accueil 7293, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France. 4. Department of Endocrinology, Diabetes, and Nutrition, Montpellier University Hospital, Montpellier, France; Laboratory of Cell Therapy of Diabetes, Institute of Functional Genomics, Mixed Research Unit, French National Center for Scientific Research 5203, Inserm U1191, University of Montpellier, Montpellier, France. 5. Centre Hospitalier Universitaire Jean Minjoz, Service d'Endocrinologie-Métabolisme et Diabétologie-Nutrition, Besançon, France. 6. Service d'Endocrinologie Diabète Nutrition, Hospices Civils de Lyon, Groupement Hospitalier Centre, Université de Lyon, Lyon, France. 7. Service de Néphrologie, Centre Hospitalier Universitaire de Nancy, Nancy, France. 8. Department of Surgery, Islet Isolation, and Transplantation, Geneva University Hospitals, Geneva, Switzerland. 9. French National Center for Scientific Research, Grenoble Alpes University, Grenoble, France; Department of Public Health, Grenoble Alpes University, Grenoble, France; Laboratoire des Techniques de l'Ingénierie Médicale et de la Complexité-Informatique, Mathématiques et Applications de Grenoble, Grenoble, France. 10. Pôle de Santé Publique Service Evaluation Economique en Santé, Hospices Civils de Lyon, Groupement Hospitalier Centre, Université de Lyon, Lyon, France; F-69003, EA 7425 Health Services and Performance Research, Public Health Service and Health Economic Evaluation, Claude Bernard University Lyon 1, Lyon, France. 11. Department of Nephrology, Grenoble Alpes University, Grenoble, France. 12. Department of Clinical Trial Surveillance, Direction of Clinical Research and Innovation, Grenoble Alpes University, Grenoble, France. 13. Department of Diabetes, Sud-Francilien Hospital, Corbeil-Essonnes, France; Université Paris-Sud, Orsay, France. 14. Service de Transplantation, Néphrologie et Immunologie Clinique, Hospices Civils de Lyon, Groupement Hospitalier Centre, Université de Lyon, Lyon, France. 15. Cellular Therapy Unit, National Blood Service Rhône-Alpes, Grenoble University Hospital, Grenoble Alpes University, Grenoble, France. 16. Service d'Urologie et de Chirurgie de la Transplantation, Hospices Civils de Lyon, Groupement Hospitalier Centre, Université de Lyon, Lyon, France. 17. Department of Endocrinology, Diabetes, and Nutrition, Grenoble Alpes University, Grenoble, France; Inserm U1055, Laboratory of Fundamental and Applied Bioenergetics Grenoble, Grenoble, France.
Abstract
BACKGROUND:Islet transplantation is indicated for patients with type 1 diabetes with severe hypoglycaemia or after kidney transplantation. We did a randomised trial to assess the efficacy and safety of islet transplantation compared with insulin therapy in these patients. METHODS: In this multicentre, open-label, randomised controlled trial, we randomly assigned (1:1) patients with type 1 diabetes at 15 university hospitals to receiveimmediate islet transplantation or intensive insulin therapy (followed by delayed islet transplantation). Eligible patients were aged 18-65 years and had severe hypoglycaemia or hypoglycaemia unawareness, or kidney grafts with poor glycaemic control. We used computer-generated randomisation, stratified by centre and type of patient. Islet recipients were scheduled to receive 11 000 islet equivalents per kg bodyweight in one to three infusions. The primary outcome was proportion of patients with a modified β-score (in which an overall score of 0 was not allocated when stimulated C-peptide was negative) of 6 or higher at 6 months after first islet infusion in the immediate transplantation group or 6 months after randomisation in the insulin group. The primary analysis included all patients who received the allocated intervention; safety was assessed in all patients who received islet infusions. This trial is registered with ClinicalTrials.gov, number NCT01148680, and is completed. FINDINGS:Between July 8, 2010, and July 29, 2013, 50 patients were randomly assigned to immediate islet transplantation (n=26) or insulin treatment (n=24), of whom three (one in the immediate islet transplantation group and two in the insulin therapy group) did not receive the allocated intervention. Median follow-up was 184 days (IQR 181-186) in the immediate transplantation group and 185 days (172-201) in the insulin therapy group. At 6 months, 16 (64% [95% CI 43-82]) of 25 patients in the immediate islet transplantation group had a modified β-score of 6 or higher versus none (0% [0-15]) of the 22 patients in the insulin group (p<0·0001). At 12 months after first infusion, bleeding complications had occurred in four (7% [2-18]) of 55 infusions, and a decrease in median glomerular filtration rate from 90·5 mL/min (IQR 76·6-94·0) to 71·8 mL/min (59·0-89·0) was observed in islet recipients who had not previously received a kidney graft and from 63·0 mL/min (55·0-71·0) to 57·0 mL/min (45·5-65·1) in islet recipients who had previously received a kidney graft. INTERPRETATION: For the indications assessed in this study, islet transplantation effectively improves metabolic outcomes. Although studies with longer-term follow-up are needed, islet transplantation seems to be a valid option for patients with severe, unstable type 1 diabetes who are not responding to intensive medical treatments. However, immunosuppression can affect kidney function, necessitating careful selection of patients. FUNDING: Programme Hospitalier de Recherche Clinique grant from the French Government.
RCT Entities:
BACKGROUND: Islet transplantation is indicated for patients with type 1 diabetes with severe hypoglycaemia or after kidney transplantation. We did a randomised trial to assess the efficacy and safety of islet transplantation compared with insulin therapy in these patients. METHODS: In this multicentre, open-label, randomised controlled trial, we randomly assigned (1:1) patients with type 1 diabetes at 15 university hospitals to receive immediate islet transplantation or intensive insulin therapy (followed by delayed islet transplantation). Eligible patients were aged 18-65 years and had severe hypoglycaemia or hypoglycaemia unawareness, or kidney grafts with poor glycaemic control. We used computer-generated randomisation, stratified by centre and type of patient. Islet recipients were scheduled to receive 11 000 islet equivalents per kg bodyweight in one to three infusions. The primary outcome was proportion of patients with a modified β-score (in which an overall score of 0 was not allocated when stimulated C-peptide was negative) of 6 or higher at 6 months after first islet infusion in the immediate transplantation group or 6 months after randomisation in the insulin group. The primary analysis included all patients who received the allocated intervention; safety was assessed in all patients who received islet infusions. This trial is registered with ClinicalTrials.gov, number NCT01148680, and is completed. FINDINGS: Between July 8, 2010, and July 29, 2013, 50 patients were randomly assigned to immediate islet transplantation (n=26) or insulin treatment (n=24), of whom three (one in the immediate islet transplantation group and two in the insulin therapy group) did not receive the allocated intervention. Median follow-up was 184 days (IQR 181-186) in the immediate transplantation group and 185 days (172-201) in the insulin therapy group. At 6 months, 16 (64% [95% CI 43-82]) of 25 patients in the immediate islet transplantation group had a modified β-score of 6 or higher versus none (0% [0-15]) of the 22 patients in the insulin group (p<0·0001). At 12 months after first infusion, bleeding complications had occurred in four (7% [2-18]) of 55 infusions, and a decrease in median glomerular filtration rate from 90·5 mL/min (IQR 76·6-94·0) to 71·8 mL/min (59·0-89·0) was observed in islet recipients who had not previously received a kidney graft and from 63·0 mL/min (55·0-71·0) to 57·0 mL/min (45·5-65·1) in islet recipients who had previously received a kidney graft. INTERPRETATION: For the indications assessed in this study, islet transplantation effectively improves metabolic outcomes. Although studies with longer-term follow-up are needed, islet transplantation seems to be a valid option for patients with severe, unstable type 1 diabetes who are not responding to intensive medical treatments. However, immunosuppression can affect kidney function, necessitating careful selection of patients. FUNDING: Programme Hospitalier de Recherche Clinique grant from the French Government.
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