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 dia-betes mellitus. N Engl J Med 2012;366:433-42.
Appendix- Table of Contents
List of all study authors……….………..2
Supplementary figures ………3
Supplementary table ……….6
Figure and table legends ……….8
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 RennesFRA, 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
Supplementary Figure S2 (A-B)
A.
Supplementary Figure S3 (A-B)
A.
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] 239 268 260 767
Total number of adverse events 309 328 297 934
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] 8 16 21 45
Total number of serious adverse events 8 16 26 50
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] 11 24 13 48
Total number of related adverse events 14 31 15 60
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
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
(benign) 1 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
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
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 1.054 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
