Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Ludvigsson J, Krisky D, Casas R, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med 2012;366:

2 Appendix- Table of Contents List of all study authors...2 Supplementary figures 3 Supplementary table.6 Figure and table legends.8 Additional Text..9

3 Appendix Co-authors Ulf Samuelsson Linköping SWE, Helena Elding Larsson Malmö SWE, Jan Åman Örebro SWE, Gunilla Kärdell Gävle SWE, Jan Neiderud Helsingborg SWE, Göran Lundström Kalmar SWE, Eva Albinsson Karlstad SWE, Annelie Carlsson Lund SWE, Maria Nordvall Norrköping SWE, Hans Fors Trollhättan SWE, Carl-Göran Arvidsson Västerås SWE, Stig Edvardson Växjö SWE, Ragnar Hanås Uddevalla SWE, Karin Larsson Kristianstad SWE, Björn Rathsman Stockholm SWE, Henrik Forsgren Hudiksvall SWE, Helena Desaix Borås SWE, Gun Forsander Göteborg SWE, Nils-Östen Nilsson Halmstad SWE, Carl-Göran Åkesson Jönköping SWE, Päivi Keskinen Tampere FIN, Riitta Veijola Oulu FIN, Timo Talvitie Seinäjoki FIN, Klemens Raile Berlin GER, Thomas Kapellen Leipzig GER, Walter Burger Berlin GER, Andreas Neu Tübingen GER, Ilse Engelsberger Bochum GER, Bettina Heidtmann Hamburg GER, Suzanne Bechtold München GER, David Leslie London UK, Francesco Chiarelli Chieti ITA, Alessandro Cicognani Bologna ITA, Giuseppe Chiumello Milan ITA, Franco Cerutti Torino ITA, Gian Vincenzo Zuccotti Milan ITA, Ana Gomez Gila Sevilla ESP, Itxaso Rica Baracaldo ESP, Raquel Barrio Madrid ESP, Maria Clemente Barcelona ESP, Maria José López Garcia Valencia ESP, Mercedes Rodriguez Zaragoza ESP, Isabel Gonzalez Madrid ESP, Juan Pedro Lopez Siguero Malaga ESP, Mirentxu Oyarzabal Pamplona ESP, H.M. Reeser The Hague NL, Roos Nuboer Amersfoort NL, Dr. Pauline Stouthart Sittard-Geleen NL, Natasa Bratina Ljubljana SLO, Nina Bratanic MD Ljubljana SLO, Marc de Kerdanet Rennes FRA, Jacques Weill Lille Sud FRA, Nicole Ser Toulouse FRA, Pascal Barat Bordeaux FRA, Anne Marie Bertrand Besançon FRA, Jean-Claude Carel Paris FRA, Rachel Reynaud Marseilles FRA, Regis Coutant Angers FRA, and Sabine Baron Nantes FRA.

4 Supplementary Figure S1

5 Supplementary Figure S2 (A-B) A. B.

6 Supplementary Figure S3 (A-B) A. B.

7 Supplementary Table S1 4 Dose Regimen (n=111) 2 Dose Regimen (n=108) Placebo (n=115) Total (n=334) Total number of patients in the period 111 (100%) 108 (100%) 115 (100%) 334 (100%) Total number of unique adverse events [a] Total number of adverse events Total number of patients with at least one adverse event 90 (81%) 84 (78%) 89 (77%) 263 (79%) Total number of unique serious adverse events [a] Total number of serious adverse events Total number of patients with at least one serious adverse event 6 (5%) 13 (12%) 13 (11%) 32 (10%) Total number of unique related adverse events [a] Total number of related adverse events Total number of patients with at least one related adverse event 11 (10%) 17 (16%) 11 (10%) 39 (12%) Total number of patients with at least one adverse event leading to discontinuation of study drug 1 (1%) 1 (1%) 2 (1%)

8 Supplementary Table S2 4 dose regimen 2 dose regimen Placebo Adverse Event # Adverse Event # Adverse Event # Hypoglycemic Event 2 Gastroenteritis 3 Hypoglycemic Event 4 Diabetic Ketoacidosis 1 Diabetes Inadequate Control 3 Intentional Insulin Overdose 3 Upper Limb Fracture 1 Hypoglycemic Event 2 Diabetes Inadequate Control 3 Knee Operation 1 Appendicitis 1 Diabetic Ketoacidosis 2 Autoimmune Hepatitis 1 Reactive Arthritis 1 Nausea 2 Diabetes Inadequate Control 1 Migraine 1 Hyperglycemia 2 Gastroenteritis 1 Diabetic Ketoacidosis 1 Mental Disorder 2 Hyperglycemia 1 Vomiting 2 Pyrexia 1 Tibia Fracture 1 Depression 1 Ovarian germ cell teratoma 1 (benign) Anorexia 1 Diarrhea 1 Upper Abdominal Pain 1 Drug Abuse 1 Membranous Glomerulonephritis 1 Dyspnea 1 Drug Delivery Device Implantation 1 Pain in extremity 1 Gastroenteritis 1

9 Supplementary Figure Legends Figure S1. Exploratory Analyses for combined two and four dose regimen male subjects Figure S2. Subgroup Analyses for combined two and four dose regimen male subjects. (A) Prespecified Analyses (B) Exploratory analyses Figure S3. Subgroup Analyses for combined two and four dose regimen male subjects. (A) Prespecified Analyses (B) Exploratory analyses Table S1. Summary of Adverse Events Between Baseline and 15 Month Visit (all subjects) Table S2. Descriptive Serious Adverse Event Table

10 Additional Text In order to better understand the smaller treatment effect in this study compared to the previous Phase II study additional exploratory analyses of efficacy were performed. The previous Phase II had treatment administration performed in the months of March and April, so a subgroup analysis was performed on patients who received their first or second injection in those months. These patients (n=82) demonstrated an estimate of treatment ratio of 1.51 (p=0.0244) (Fig.S1) compared to a ratio of for those who did not have their first or second injection in March and April (n=235),(p=0.63). Another difference between the Phase II study and the current study was the administration of vaccines during the study period. During this trial there was an emergence of a pandemic influenza strain that led to vaccinations within a period where vaccination was not recommended. Patients who did not receive influenza vaccinations within 150 days after the first injection of study medication (n=261) showed an estimate of treatment ratio of 1.20 (p=0.0713),(fig.s1) while patients with a vaccination within 150 days (n=56) had a treatment ratio of ( p=0.87). Supplementary Figures S2 and S3 have additional data.