A Phase IIb, 2-Arm, Randomized, Double-blind, Placebo-Controlled, Multicentre Study to Optimize Diamyd Therapy Administered Into Lymph Nodes Combined With Oral Vitamin D to Investigate the Impact on the Progression of Type 1 Diabetes
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1, Diabetes Mellitus, Autoimmune Diseases, Metabolic Disease, Glucose Metabolism Disorders, Immune System Diseases, Endocrine System Diseases, Juvenile Diabetes, Insulin Dependent Diabetes, Autoimmune Diabetes, Vitamin D, Physiological Effects of Drugs
Sponsor: Diamyd Medical AB

 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
A Phase IIb, 2-Arm, Randomized, Double-blind, Placebo-Controlled, 
Multicentre Study to Optimize Diamyd® Therapy Administered into 
Lymph Nodes Combined with Oral Vitamin D to Investigate the 
Impact on the Progression of Type 1 Diabetes 
 
Study No. DIAGNODE-2 
EudraCT Number: 2017-001861-25 
Study Development Phase:  IIb 
Version 8: May 15, 2020 
 
Sponsor: 
Diamyd Medical AB 
 
 
 
 
 
 
 
 
 
 
Coordinating investigator:  
 
 
 
 
 
 
 
 
 
 
Contract Research Organization: 
 
 
 
 
 
 
Planned start date: 
 
Q4, 2017 
 
 
STUDY PROTOCOL VERSION TABLE 
Version 1:  
 
May 03, 2017 
Version 2: 
Version 3:  
June 16, 2017 
August 21, 2017 
Version 4: 
November 03, 2017 
Version 5:  
February 26, 2018 
Version 6: 
June 28, 2018 
Version 7:  
June 18, 2019 
Version 8: 
May 15, 2020 
 
 
CONFIDENTIALITY STATEMENT 
This material is confidential and the property of Sponsor. Its contents must not be disclosed or used 
except as authorized in writing by Sponsor. 
 
 
 
NCT: 03345004

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CONFIDENTIAL 
 
1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS .............................................................................................................. 3 
2 
SYNOPSIS OF PROPOSED DIAGNODE-2 STUDY ............................................................... 6 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF STUDY SPECIFIC 
TERMINOLOGY ................................................................................................................................... 9 
4 
INTRODUCTION AND RATIONALE FOR THE STUDY ................................................... 11 
4.1 
INTRODUCTION ......................................................................................................................... 11 
4.1.1 
GAD and Diamyd, Completed Studies .......................................................................... 13 
4.1.2 
Ongoing Study with Diamyd Administered as Intralymphatic Injections – 
DIAGNODE-1 .............................................................................................................................. 15 
4.2 
RATIONALE FOR TREATMENT OF TYPE 1 DIABETES PATIENTS WITH DIAMYD AND VITAMIN D 16 
4.3 
RATIONALE FOR USE OF INTRALYMPHATIC ROUTE OF ADMINISTRATION OF DIAMYD.............. 17 
5 
RISK-BENEFIT ANALYSIS ..................................................................................................... 18 
5.1 
RISKS OF INTRALYMPHATIC DIAMYD ....................................................................................... 18 
5.2 
RISKS OF VITAMIN D ................................................................................................................ 18 
5.3 
RISKS OF COMBINING DIAMYD AND VITAMIN D ....................................................................... 19 
5.4 
JUSTIFICATION – RISK-BENEFIT ................................................................................................ 19 
6 
TRIAL OBJECTIVES AND PURPOSE................................................................................... 20 
6.1 
AIM OF PRESENT STUDY ........................................................................................................... 20 
6.2 
PRIMARY OBJECTIVE ................................................................................................................ 20 
6.3 
SECONDARY OBJECTIVES .......................................................................................................... 20 
6.4 
ENDPOINTS ............................................................................................................................... 20 
6.4.1 
Primary Endpoint .......................................................................................................... 20 
6.4.2 
Secondary Endpoints ..................................................................................................... 20 
6.4.3 
Exploratory Endpoints ................................................................................................... 21 
7 
TRIAL DESIGN .......................................................................................................................... 23 
7.1 
DESCRIPTION OF THE STUDY DESIGN AND PROCEDURES .......................................................... 23 
7.1.1 
Study Procedures ........................................................................................................... 28 
7.2 
PATIENT DIARY ........................................................................................................................ 33 
7.3 
STUDY STOPPING CRITERIA ...................................................................................................... 33 
7.4 
DECISION CRITERIA .................................................................................................................. 33 
7.5 
MANAGEMENT OF THE DISEASE ................................................................................................ 33 
7.6 
DATA SAFETY MONITORING BOARD ......................................................................................... 34 
8 
STUDY POPULATION ............................................................................................................. 35 
8.1 
INCLUSION CRITERIA ................................................................................................................ 35 
8.2 
EXCLUSION CRITERIA ............................................................................................................... 35 
8.3 
RECRUITMENT AND SCREENING ................................................................................................ 36 
8.4 
PATIENT WITHDRAWAL CRITERIA ............................................................................................ 36 
8.5 
PATIENT WITHDRAWAL ............................................................................................................ 37 
9 
STUDY ASSESSMENTS ........................................................................................................... 39 
9.1 
ASSESSMENT OF VARIABLES OF DIABETES STATUS .................................................................. 39 
9.1.1 
Mixed Meal Tolerance Test ........................................................................................... 39 
9.1.2 
Hemoglobin A1c ............................................................................................................ 39 
9.1.3 
Fasting Glucose and Fasting C-Peptide ....................................................................... 39 
9.1.4 
Glycemic Fluctuations/Variability ................................................................................ 40 
9.2 
ASSESSMENT OF SAFETY VARIABLES ....................................................................................... 40 
9.2.1 
Adverse Events ............................................................................................................... 40 
9.2.2 
Physical Examination .................................................................................................... 40 
9.2.3 
Neurological Examination ............................................................................................ 41 
9.2.4 
Vital Signs ...................................................................................................................... 41 
9.2.5 
Laboratory Safety Assessments ..................................................................................... 42 
9.3 
IMMUNE SYSTEM ASSESSMENTS ............................................................................................... 42 

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9.3.1 
GAD65 Antibody Titer ................................................................................................... 42 
9.3.2 
Bioanalytical Method ..................................................................................................... 42 
9.4 
ASSESSMENT OF GENETIC STATUS ............................................................................................ 43 
9.5 
MEASUREMENT OF VITAMIN D STATUS .................................................................................... 43 
9.5.1 
Blood Sampling Procedures .......................................................................................... 43 
9.6 
COVID-19 SEROLOGICAL TESTING ............................................................................................. 43 
9.7 
ASSESSMENT OF QUALITY OF LIFE............................................................................................ 44 
9.8 
ASSESSMENT OF PUBERTAL STAGE AND CONCOMITANT MEDICATION ..................................... 44 
9.9 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ..................................................... 44 
9.9.1 
Demographics and Baseline Data ................................................................................. 44 
9.9.2 
Medical History .............................................................................................................. 44 
9.9.3 
Family History of T1D ................................................................................................... 44 
10 
TREATMENT OF PATIENTS ................................................................................................. 45 
10.1 STUDY TREATMENT .................................................................................................................. 45 
10.1.1 
Method of Assigning Patients to Treatment Groups .................................................... 45 
10.1.2 
Blinding and Code Breaking ......................................................................................... 45 
10.1.3 
Study Medication ........................................................................................................... 47 
10.1.4 
Supply, Packaging, Handling and Storage ................................................................... 47 
10.2 TREATMENT COMPLIANCE ........................................................................................................ 48 
10.3 STUDY MEDICATION ACCOUNTABILITY .................................................................................... 48 
10.4 CONCOMITANT THERAPY .......................................................................................................... 48 
10.5 POST STUDY TREATMENT ......................................................................................................... 48 
11 
ADVERSE EVENTS .................................................................................................................. 49 
11.1 DEFINITIONS OF ADVERSE EVENTS (AE) .................................................................................. 49 
11.2 SERIOUSNESS ............................................................................................................................ 49 
11.3 INTENSITY ................................................................................................................................. 49 
11.4 RELATIONSHIP TO STUDY MEDICATION .................................................................................... 50 
11.5 REPORTING OF ADVERSE EVENTS ............................................................................................. 50 
11.6 TIMELINES AND REPORTING OF SAE ........................................................................................ 50 
11.7 UNRESOLVED EVENTS .............................................................................................................. 51 
11.8 PREGNANCY REPORT FORM ...................................................................................................... 52 
11.9 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................................................................... 52 
12 
DATA HANDLING .................................................................................................................... 53 
12.1 DATA MANAGEMENT ................................................................................................................ 53 
13 
STATISTICAL METHODS ...................................................................................................... 54 
13.1 ESTIMATION OF SAMPLE SIZE ................................................................................................... 54 
13.2 STATISTICAL ANALYSES ........................................................................................................... 54 
13.2.1 
Data Sets to be Analyzed ................................................................................................ 54 
13.2.2 
Statistical and Analytical Plan ...................................................................................... 55 
13.2.3 
Hypotheses and Statistical Methods .............................................................................. 55 
13.2.4 
Level of Significance, Multiple Comparisons and Multiplicity .................................... 60 
13.2.5 
Adjustment for Covariates ............................................................................................. 60 
13.2.6 
Handling of Dropouts and Missing Data ...................................................................... 60 
13.2.7 
Multicenter Studies ........................................................................................................ 60 
13.2.8 
Examination of Subgroups ............................................................................................ 60 
13.2.9 
Interim Analysis and Data Monitoring ......................................................................... 60 
13.2.10 Deviation(s) from the Statistical Analysis Plan ............................................................ 60 
14 
REGULATORY AND ADMINISTRATIVE PROCEDURES ............................................... 61 
14.1 ETHICS COMMITTEES AND COMPETENT AUTHORITIES .............................................................. 61 
14.2 PATIENT INFORMATION / INFORMED CONSENT ......................................................................... 62 
14.3 PATIENT CONFIDENTIALITY ...................................................................................................... 62 
14.4 PATIENT TREATMENT PLAN ...................................................................................................... 62 
14.5 GCP .......................................................................................................................................... 63 
14.6 RECORD RETENTION ................................................................................................................. 63 
14.7 MONITORING / QUALITY CONTROL ........................................................................................... 63 

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14.8 SOURCE DATA .......................................................................................................................... 63 
14.9 QUALITY ASSURANCE AND INSURANCE .................................................................................... 64 
15 
END OF TRIAL .......................................................................................................................... 65 
15.1 STUDY REPORT ......................................................................................................................... 65 
15.2 STUDY STOPPING CRITERIA ...................................................................................................... 65 
15.3 PUBLICATION ............................................................................................................................ 65 
16 
LIST OF REFERENCES ........................................................................................................... 66 
17 
SIGNATURES............................................................................................................................. 70 
18 
CLINICAL STUDY PROTOCOL AGREEMENT FORM .................................................... 71 
 
LIST OF TABLES 
 
Table 1 Schedule of Patient Visits for DIAGNODE-2 ............................................. 24 
Table 2 Schedule of Study Events, Main Study Period ............................................ 25 
Table 3    Schedule of Study Events, Extension Study Period .................................... 27 
 

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2 
 SYNOPSIS OF PROPOSED DIAGNODE-2 STUDY  
 
Name of Sponsor/Company 
Diamyd Medical AB 
Individual Study Table Referring to 
Part of Dossier in which the 
Individual Study or Study Table is 
Presented: 
 
 
 
 
Volume: 
Reference: 
 
(For National 
Authority Use 
Only) 
 
 
Name of Finished Product:  
DIAMYD® 
D-vitamin 
 
 
Name of Active Ingredient:  
 
Title of Study: A Phase IIb, 2-Arm, Randomized, Double-blind, Placebo-Controlled, Multicentre Study 
to Optimize Diamyd® Therapy Administered into Lymph Nodes Combined with Oral Vitamin D to 
Investigate the Impact on the Progression of Type 1 diabetes  
Protocol Number: DIAGNODE-2 
Investigators and Study Centre: Approximately 22 sites in Sweden, Spain, Czech Republic and the 
Netherlands including approximately 106 patients 
Phase of Development: Phase IIb 
Objectives: 
Primary objective 
The primary objective is to evaluate the efficacy of Diamyd, administered into lymph nodes in 
combination with an oral vitamin D regimen, compared to placebo in terms of preserving endogenous 
insulin secretion as measured by C-peptide. 
 
Secondary objectives 
The secondary objectives are to compare Diamyd, administered into lymph nodes in combination with an 
oral vitamin D regimen and placebo treatment with respect to the effects on the diabetes status, treatment 
safety, immune system and quality of life (QoL) of the patients. 
Study Design: 
The study is a 2-arm, randomized, double-blind, placebo-controlled, multicenter, clinical trial. Eligible 
patients will receive injections of Diamyd/placebo into an inguinal lymph gland at three occasions, with 
one month intervals in combination with an oral vitamin D/placebo regimen (starting 1 month ahead of 
injections) during 4 months. All patients will continue to receive intensive insulin treatment from their 
personal physicians during the whole study period. The patients will be followed in a blinded manner for 
a total of 15 months. All patients that are ongoing, i.e. have not performed Visit 7 (15 months visit) when 
protocol version 7 is approved and implemented, will be asked to participate in the Extension Study 
Period which include Visit 8 at month 24.  
Selection of Patients: Patients must be ≥12 and <25 years old, and diagnosed with Type 1 diabetes 
(T1D) within the previous 6 months at the time of screening. Patients will be eligible for enrolment if 
fasting C-peptide is ≥0.12 nmol/L (0.36 ng/mL) and elevated levels of GAD65A, i.e. antibodies to 
glutamic acid decarboxylase (GAD) with molecular weight of 65 kDa (GAD65) are present. 
Number of Patients Planned: Approximately 106 patients will be enrolled. To ensure that 
106 patients are screened and enrolled approximately 127 patients will be screened. 

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EudraCT number: 2017-001861-25 
VERSION 8: MAY 15, 2020 
 
CONFIDENTIAL 
 
Name of Sponsor/Company 
Diamyd Medical AB 
Individual Study Table Referring to 
Part of Dossier in which the 
Individual Study or Study Table is 
Presented: 
 
 
 
 
Volume: 
Reference: 
 
(For National 
Authority Use 
Only) 
 
 
Name of Finished Product:  
DIAMYD® 
D-vitamin 
 
 
Name of Active Ingredient:  
 
Description of Treatment Groups: 
The patients will be assessed for eligibility at the screening visit (Visit 1) 2 to 4 weeks prior to start of 
oral treatment with vitamin D. On Visit 2 (Day 1), patients eligible for the study will be randomized to 1 
of 2 treatment groups: 
• 
Approximately 53 patients will be assigned to receive i) three (3) intralymphatic injections with 
4 µg Diamyd on Days 30, 60, and 90 and; ii) oral vitamin D 2000 IE daily for 4 months (from 
Day 1 through Day 120) 
• 
Approximately 53 patients will be assigned to receive i) three (3) intralymphatic injections of 
Placebo for Diamyd on Days 30, 60, and 90 and; ii) oral Placebo for vitamin D once a day for 
4 months (from Day 1 through Day 120) 

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CONFIDENTIAL 
 
Name of Sponsor/Company 
Diamyd Medical AB 
Individual Study Table Referring to 
Part of Dossier in which the 
Individual Study or Study Table is 
Presented: 
 
 
 
 
Volume: 
Reference: 
 
(For National 
Authority Use 
Only) 
 
 
Name of Finished Product:  
DIAMYD® 
D-vitamin 
 
 
Name of Active Ingredient:  
 
Endpoints: 
Primary Endpoint: 
• 
Change in C-peptide (Area Under the Curve [AUC]mean 0-120 min) during a Mixed Meal Tolerance 
Test (MMTT) between baseline to 15 months. 
Key Secondary Endpoints: 
• 
Change in insulin-dose-adjusted HbA1c (IDAA1c) between baseline and 15 months  
• 
Change in Hemoglobin A1c (HbA1c) between baseline and 15 months 
• 
Change in daily exogenous insulin consumption between baseline and 15 months. 
 
Secondary endpoints:  
• 
Other variables that indicate Diabetes Status such as plasma C-peptide, variability of blood 
sugar, and number of self-reported hypoglycemia. 
• 
Variables that indicate treatment safety such as occurrence of adverse events (AEs), physical 
examinations, hematology, urine analysis, injection site reactions, GAD65A titer, vital signs and 
clinical chemistry. 
• 
Variables that indicate effects on the immune system such as serum autoantibodies (and 
isotypes) to GAD65, serum cytokine levels, secretion of cytokines by immune cells in response 
to GAD65-stimulation, and proportions of immune cells in blood. 
• 
Measurements of patient QoL by questionnaire. 
Exploratory Endpoints: 
• 
All data collected at the 24-month follow-up visit will be regarded as exploratory endpoints.  
Sample size:   
A total sample size of 106 patients is planned for a 1:1 randomization in order to provide 90% power to 
detect a 50% difference in geometric mean C-peptide (AUCmean 0-120 min) at 15 months between the active 
arm and placebo arm using a two-sided test at the 0.05 level, with 10% loss to follow-up. This is based 
upon a t-test employing ln(X+1) normalizing transformation of C-peptide (AUCmean 0-120 min) during an 
MMTT at 15 months and assumed mean and standard deviation estimates, on the transformed scale, of 
0.134 and 0.20 respectively.  
Analysis of Primary endpoint variable:   
The mean change in log-transformed values will be analyzed using Mixed Model Repeated Measures 
(MMRM). The model for analysis will include fixed, categorical effects of treatment, randomization 
strata (GAD65A level), visit and treatment by visit interaction, as well as the continuous, fixed covariates 
of baseline value.  
Analysis of Key Secondary endpoint variables:  
Key secondary efficacy endpoint variables will be analysed with the same MMRM model as the primary 
efficacy endpoint. 
Analysis of Secondary endpoint variables:  
Continuous secondary diabetes status variables will be compared using the same MMRM model as for 
the primary efficacy endpoint. 
 
 

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CONFIDENTIAL 
 
Name of Sponsor/Company 
Diamyd Medical AB 
Individual Study Table Referring to 
Part of Dossier in which the 
Individual Study or Study Table is 
Presented: 
 
 
 
 
Volume: 
Reference: 
 
(For National 
Authority Use 
Only) 
 
 
Name of Finished Product:  
DIAMYD® 
D-vitamin 
 
 
Name of Active Ingredient:  
Recombinant Human Glutamic 
Acid Decarboxylase (rhGAD65) 
Calciferol  
Categorical secondary endpoints will be presented using summary statistics and p-value from stratified 
Cochran/Mantel-Haenszel Test. 
For immunological secondary endpoints summary statistics will be accompanied with p-values from non-
parametric statistical tests 
Analysis of the QoL data obtained within the study will follow the EQ-5D-5L User guide. 
 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF STUDY SPECIFIC 
TERMINOLOGY 
 
1,25(OH)2D3 
1α,25-dihydroxyvitamin D3 also called calcitriol 
AE 
Adverse Event 
Alum 
Aluminum hydroxide 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Curve 
AUCmean 0-120 min 
AUC mean 0-120 minutes 
BMI 
Body Mass Index 
BP 
Blood Pressure 
DKA 
Diabetic Ketoacidosis 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
DCCT 
Diabetes Control and Complications Trial 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
ELISPOT 
Enzyme Linked Immunosorbent Spot Forming Cell Assay  
FAS 
Full analysis set 
FGM 
Flash Glucose Monitoring 
GABA 
Gamma-amino Butyric Acid 
GAD 
Glutamic acid decarboxylase 
GAD65 
GAD with molecular mass 65 kDa 
GAD65A 
Antibodies to GAD65 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c  
HCG 
Human Chorionic Gonadotropin 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
IAA 
Insulin Autoantibody 
IA-2 
Insulinoma-associated Protein 2 

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IA-2A 
Insulinoma-associated Protein 2 antibodies 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IDAA1c 
Insulin-Dose-Adjusted HbA1c 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
IWRS 
Interactive Web Response System 
LADA 
Latent Autoimmune Diabetes in Adults 
LS 
Least Square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
MMTT 
Mixed Meal Tolerance Test 
NCS/CS 
Not Clinically Significant/Clinically Significant 
NOD 
Non-obese Diabetic  
PBMC 
Peripheral Blood Mononuclear Cells 
PPS 
Per-Protocol Set 
QALY 
Quality Adjusted Life Years 
QoL 
Quality of Life 
rhGAD65 
Recombinant Human GAD65 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1D 
Type 1 Diabetes 
T2D 
Type 2 Diabetes 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
 
Th1 
T Helper Cell Type 1 
Th2 
T Helper Cell Type 2 
TNF 
Tumour Necrosis Factor 
 

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4 
INTRODUCTION AND RATIONALE FOR THE STUDY 
4.1 
Introduction  
Type 1 diabetes (T1D) belongs to the group of medical disorders classified as 
“autoimmune” due to a pathologic feature involving an inappropriate immunological 
recognition of the body’s own tissues. This abnormal immune response, in the case of 
T1D, results in the destruction of insulin-secreting pancreatic beta cells which in turn 
leads to a lifelong dependence on exogenous insulin treatment and exposure to both 
the acute and late complications of T1D. T1D is a particular burden to children and 
their families, representing by far the most common chronic, serious, life-threatening 
disease among children and adolescents in Sweden, but common also among adults, 
and tends to become an extremely serious global problem. 
 
By the time a T1D patient is diagnosed, 70-90% of pancreatic islet beta cell function 
has been lost due to autoimmune responses against specific beta cell antigens. Over 
time the ability to produce endogenous insulin is reduced even further. As this 
happens a T1D patient is more and more reliant on exogenous insulin and is at greater 
risk for both acute and long term complications of T1D. In the more acute 
manifestation of T1D, or in the absence of treatment, the lack of insulin can result in 
diabetic ketoacidosis (DKA), a potentially life-threatening medical emergency. 
Insulin therapy can dramatically reduce the possibility of death from DKA but even 
patients adequately treated with insulin are still at increased risk to a number of acute 
and long-term (chronic) complications. Acute complications include DKA and severe 
hypoglycemia. Long-term complications of T1D include microvascular, 
macrovascular and neurologic complications that increase morbidity as well as 
mortality. Studies have shown that retained residual insulin production is associated 
with a reduction in DKA and hypoglycemic risk as well as in the development of 
long-term complications.  
 
Although the use of insulin has dramatically improved the survival of patients with 
T1D, insulin does not represent a cure as individuals with the disorder, even if well 
managed, display marked increases in the frequency of debilitating and even life-
threatening complications. The severity of these complications makes the 
development of a therapy allowing for beta cell preservation of great urgency for 
patients and caregivers. The world-wide incidence of T1D is increasing and despite 
the significant progress that has been made in its treatment, T1D still represents a 
severe burden on the individual and on society as well. Any intervention, which can 
stop or delay the complete loss of functional residual beta-cell mass would be 
significant as it would provide protection against hypoglycemia and keto-acidosis, 
improve metabolic control, and a delay and reduction in the micro and macro-vascular 
complications of diabetes.1,2,3,4. 
 
In summary, T1D without residual insulin secretion is a dangerous disease with 
increased mortality despite a lifetime of intense treatment. There is currently no 
approved method or medicament to halt or slow the immune destruction of remaining 
pancreatic islet beta cells. Such a treatment would be of great benefit for all newly 
diagnosed T1D patients in the world, as well for the society.  
 
The etiology of T1D is still unknown. Genetic factors, such as Human Leukocyte 
Antigen (HLA) genotypes, confer susceptibility to the disease, but other factors, both 

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genetic and environmental, are needed to initiate the autoimmune process that results 
in beta cell death. The environmental factors that either trigger the development of the 
autoimmune process or accelerate the beta cell destruction process are still to be 
defined. 
 
The destruction of the pancreatic beta cells in T1D is associated with cellular immune 
responses to the pancreatic islet cells, genetic susceptibility involving genes thought 
to modulate the immune response, and the presence of autoantibodies against several 
islet beta cell components (i.e., autoantigens)5,6 In addition, as these T1D-associated 
autoantibodies often precede the clinical onset of disease, GAD65A, i.e. 
autoantibodies directed against glutamic acid decarboxylase (GAD) with a molecular 
weight of 65 kDa (GAD65A), insulinoma-associated protein 2 (IA-2A), insulin 
autoantibody (IAA) or zinc T8 (ZnT8A) are widely recognized not only as diagnostic 
markers for autoimmune beta cell destruction, but as predictive markers for the 
disease7. 
 
Animal studies and early clinical trials have shown promise in targeting the 
autoimmune process and reversing the progress of the disease through the use of anti-
inflammatory, immunomodulatory or immunosuppressive regimens. However, no 
monotherapies have reached their primary end-points when tested in late-phase 
clinical trials. 
 
The current consensus around developing a cure for T1D is to target the etiology of 
the disease using a combination of different therapies. These therapies should 
optimally down-regulate the acute inflammatory response, tolerize the immune 
system against islet cell autoantigens and stimulate the proliferation, neogenesis and 
insulin secretion of the remaining beta cells8. 
 
The combination therapy to be evaluated in this study involves the investigational 
Antigen Specific Immunotherapy Diamyd administered directly into lymph node and 
Vitamin D administered orally. 
 
Diamyd is an investigational drug composed of the recombinant human GAD65 
(rhGAD65) protein formulated in a sterile, non-pyrogenic phosphate buffered saline 
containing the aluminum hydroxide (alum) adjuvant, Alhydrogel. The active 
ingredient, rhGAD65, is manufactured via expression in an insect cell line, followed 
by stringent purification. 
 
The underlying basis of T1D involves a “pro-inflammatory” T-cell response against 
insulin-secreting beta cells that is sufficient to cause their destruction and result in 
insufficient production of endogenous insulin. Diamyd therapy aims at intervening in 
this destructive process by modulating the immune system in a discrete, antigen-
specific fashion to prevent the destruction of beta cells. Thus, the goal of Diamyd 
therapy would be to slow down or halt the ongoing autoimmune destruction of 
pancreatic islet beta cells in order to preserve the largest possible amount of 
endogenous insulin production. 
 
In the proposed treatment regimen, exogenous oral Vitamin D treatment may improve 
the efficacy both via effects on the immune system and mechanism directly on the 
beta cells to increase beta cell function and limit the autoimmune reaction. This may 

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improve blood sugar control and at the same create a fertile field for Diamyd to 
induce long term tolerability. 
4.1.1 
GAD and Diamyd, Completed Studies 
Although the involvement of GAD in neural transmission is understood by its 
function as an enzyme converting glutamate to gamma-amino butyric acid (GABA), 
its specific and unequivocal function in pancreatic beta cells, as well as its role in the 
pathogenesis of either form of diabetes remains unclear. Indeed, the reason why GAD 
is a major autoantigen in autoimmune diabetes is not known. However, a broad body 
of the scientific community has produced convincing data from the non-obese diabetic 
(NOD) mouse model of T1D that administration of an isoform of GAD with a 
molecular mass of approximately 65kDa (GAD65) can prevent autoimmune 
destruction of pancreatic beta cells and subsequent need for exogenous insulin 
replacement9,10,11,12,13,14,15,16,17,18,19. These findings indicate the potential of Diamyd 
administration as a treatment for T1D. 
 
GAD65 is a major autoantigen in autoimmune diabetes and clinical administration of 
Diamyd aims to intervene in the autoimmune process in T1D by modulating the 
immune system via discrete, antigen-specific tolerization in order to arrest or delay 
the autoimmune destruction of pancreatic beta cells. In recent-onset T1D patients, 
such induced immune tolerization is proposed to prevent the destruction of remaining 
beta cells thereby maintaining residual insulin secretion, improving metabolic control 
and reducing the risk of acute and long-term diabetes complications. Available data 
demonstrate that even relatively modest retained insulin secretion capability is 
associated with clinically meaningful benefits including improved glycemic control, 
reduced hypoglycemia, retinopathy and nephropathy1,2,3,4. Additionally, intervening in 
the destruction of beta cells could allow for beta cell replenishment, either by 
stimulating regeneration or transplantation20. 
 
Thus, the goal of Diamyd therapy would be to dramatically slow or halt the ongoing 
autoimmune destruction of pancreatic islet beta cells in order to preserve the largest 
possible amount of endogenous insulin production. 
 
Two formulations of Diamyd have been evaluated in preclinical and clinical studies. 
The bulk Drug Substance (formulated in buffer from the manufacturing process) was 
used for initial preclinical safety studies, a skin Prick Test in T1D patients and a Phase 
I clinical trial (formulated in phosphate buffered saline). An adjuvant formulation 
based on Alhydrogel® was then developed (Diamyd®) and used in Phase II clinical 
trials. 
 
A preclinical safety evaluation program has been conducted by Diamyd Medical AB, 
Stockholm, Sweden to support the progression of Diamyd into clinical development. 
This has comprised single- and repeat-dose toxicity, local tolerance, immunotoxicity, 
and investigation of the potential for effects on behavior and 
cardiovascular/respiratory function. Evaluation of all preclinical safety studies 
performed to date have not provided concerns for clinical safety of either the bulk 
Drug Substance used for Diamyd or Diamyd itself, even at multiples of the highest 
clinically-intended dose level, nor resulted in the observation of any target organs of 
toxicity. Likewise, evaluation of the effects of Diamyd in several different animal 

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models of autoimmune disease did not indicate any potential for undesirable effects 
on the immune system. 
 
A dose-finding Phase IIa study in 47 patients with Latent Autoimmune Diabetes in 
Adults (LADA) demonstrated the safety and efficacy of Diamyd. This randomized, 
double-blind and placebo-controlled study demonstrated efficacy in preventing beta 
cell destruction in the group of patients receiving the 20 µg dose. There were no 
serious adverse events (SAEs) reported during the 6 month long main study period. 
The majority of reported Adverse Events (AEs) were due to influenza-like symptoms. 
A minority of injections resulted in injection-site reactions, which were mild and 
occurred primarily on the day of the injections. These findings support the safety of 
immuno-modulation by treatment with alum-formulated rhGAD65. The 5-year final 
follow-up investigation did not reveal any study-related SAEs21,22. 
 
In a Phase IIb, randomized, double-blind, placebo-controlled multicenter study in 
160 LADA-patients, the patients received 20 µg of rhGAD65 or placebo on 
2 occasions 4 weeks apart. The efficacy analysis was discontinued due to quality 
concerns pertaining to randomization. However, no safety concerns were raised. None 
of the SAEs reported in the study were related to the treatment. 
 
In another Phase IIb clinical trial, the efficacy and safety of Diamyd were investigated 
in children 10-18 years of age, recently diagnosed with T1D. A total of 
70 GAD65A-positive children with a recent diagnosis (<18 months duration) of T1D 
and remaining beta-cell capacity measured by C-peptide levels, were included in the 
study. The study was randomized, double-blind and placebo-controlled and 20 µg 
Diamyd was given twice 4 weeks apart. The study has provided support for the 
clinical safety of Diamyd and statistically significant and clinically relevant positive 
effect on the preservation of beta cell function (production of C-peptide) was seen 
after 30 months23. The frequency and pattern of AEs did not differ significantly 
between the placebo and active treatment group. There were no treatment-related 
SAEs reported.  
 
A 3-armed Phase III, randomized double-blind, placebo-controlled multi-center 
intervention study has been completed. In this study a total of 334 children and 
adolescents in the EU, 10-20 years of age with recent onset of T1D (within 3 months) 
was given placebo or 20 µg Diamyd in a prime-and-boost regimen on days 1 and 30 
to confirm previous Phase II results. Additionally, one arm of patients was given two 
additional single doses of 20 µg Diamyd also on days 90 and 270, to evaluate 
optimization of the treatment. This study did not fulfil the efficacy goal at the 
15 months follow-up, but significant treatment effects were observed in several 
subgroups24. A US study run in parallel with identical study design, was closed early 
due to the EU study outcome. The safety analyses performed by the Data Safety 
Monitoring Board (DSMB) with data from both the EU Phase III study and the 
parallel US Phase III study further supports the clinical safety of Diamyd 
administration in children and adolescents with T1D. In addition, an investigator 
initiated Phase II clinical intervention trial in the US and Canada, performed by T1D 
TrialNet (with National Institute of Diabetes and Digestive and Kidney Diseases 
[NIDDK] as sponsor), reported results in June 2011 and this trial did not meet its 
efficacy endpoints25. 
 

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Vitamin D has been used in patients with recent onset T1D in an effort to preserve 
residual insulin secretion. So far vitamin D alone has not been efficacious enough39,40. 
Therefore, there is reason to evaluate vitamin D, both in somewhat higher dose, and in 
combination with other therapies, as has been done in the DIAGNODE-1 study. In our 
proposed treatment regimen exogenous oral Vitamin D treatment may improve the 
efficacy both via effects on the immune system and directly on the beta cells to 
increase beta cell function and limit the autoimmune reaction. This may improve 
blood sugar control and at the same create a fertile field for Diamyd to induce long 
term tolerability. 
4.3 
Rationale for Use of Intralymphatic Route of Administration of Diamyd 
Antigen specific immunotherapy aims at presenting the antigen to the T-cells in the 
lymph nodes to get a new balance of the immune system and tolerance against the 
antigen. In the treatment of autoimmune diseases antigen has most often been given 
either orally, intranasally or subcutaneously after which antigen-presenting cells 
having moved to the lymphatic tissues will ingest and present the antigen to the cells 
of the immune system. 
 
Animal studies have shown that direct intralymphatic injections of antigen, induce a 
strong and relevant T-cell response41,42,43. In the allergy field, clinical studies have 
shown that presentation of the antigen directly into the lymph nodes seems to be more 
effective than traditional administration, allowing for lower doses and radically fewer 
numbers of treatments, and there have been no treatment-related AEs44,45,46,47. 
Inguinal lymph nodes are readily accessible in patients and the pain associated with 
the injection is rated as below that of venous puncture45. With this background one of 
the currently ongoing studies with Diamyd is investigating whether the same approach 
can be used to increase efficacy of antigen specific immunotherapy in patients in T1D 
in an open label pilot study (DIAGNODE-1). As previous studies have indicated that 
a dose of 20 µg Diamyd administered sc twice in a prime-and-boost regimen has a 
positive effect on preservation of endogenous insulin producing capacity26, and other 
studies have shown that intralymphatic administration can achieve adequate efficacy 
with 3 injections of lower antigen doses, a lower dose of 4 µg Diamyd injected 
directly into the inguinal lymph node (by help of ultrasound technique) 3 times at 
1 month intervals is expected to be adequate. This was the treatment regimen chosen 
for DIAGNODE-1. The larger proposed double-blind clinical study DIAGNODE-2 
will use the same treatment regimen to verify the results of the previous trial. 
 
 
 
 

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5 
RISK-BENEFIT ANALYSIS 
5.1 
Risks of Intralymphatic Diamyd 
Diamyd is an investigational experimental study drug (not marketed or approved) that 
has been studied in preclinical and clinical trials (Phase I through III). There are no 
risks of particular severity or seriousness anticipated based on the toxicological data 
in animals or prior studies in humans, except that patients have reported injection site 
reactions, such as e.g. itching, edema, tenderness, bruises, and pain. All patients 
recovered, and no patient was withdrawn from further treatment due to injection site 
reactions. 
 
Theoretical risks of Diamyd such as acceleration of the autoimmune process, 
undesirable effects on the immune system and neurological disease have been 
discussed and also thoroughly evaluated during several clinical trials in both children 
and adults, all clinical studies performed with Diamyd to date indicate a favorable 
safety profile for Diamyd and no neurological concerns have been raised. It is still 
possible that not yet detected side effects may be revealed in this or future clinical 
trials. 
 
The dose of 20 μg of Diamyd, administered as a prime dose with a booster dose 
1 month later or as a prime and boost on days 1 and 30 followed by 1 or 2 additional 
single doses (days 90 and 270) have been shown to be safe in man (children and 
adolescents) with few and mild adverse reactions. All dosing will take place in the 
hospital-based clinic, and handled only by trained, authorized study personnel, by 
help of ultrasound technique. 
 
Drug Products consisting of alum-formulated proteins have been injected 
intralymphatically in clinical trials in the allergy fields without concerns45,46,47. The 
immunological data gathered in the DIAGNODE-1 trial suggest that the immune 
response of intralymphatic injections are stronger than previous subcutaneous 
administrations, and the levels of antibodies to GAD65 in patient serum appear to be 
increased further than previously. This withstanding there have been no negative 
effects reported in any of the patients of DIAGNODE-127. 
 
For further detailed information about previous studies and safety please refer to the 
Diamyd Investigator’s Brochure vs 21, 2019. 
5.2 
Risks of Vitamin D 
There are no anticipated risks of vitamin D supplementation at the dose to be 
administered in this study, although toxic levels may induce hypercalcemia with 
symptoms such as tiredness, euphoria, nausea, drowsiness, weight loss, thirst, 
polyuria, nefrocalcinosis and renal failure. Additional symptoms of vitamin D toxicity 
include electrocardigraph changes, arrhythmia and pancreatitis.  
 
In the study DIABGAD-1, vitamin D 2000 IU per day is administered orally for 
15 months. This dose given to children and adolescents aged 10-18 years can be 
compared with the dose of 400 IU per day given to babies as a health recommendation 
to avoid vitamin D insufficiency. Approximately 60 patients in DIABGAD-1 have 
been randomized of whom ¾ should have received vitamin D, and only 6 AEs were 
assessed by the investigator as related to vitamin D (in 4 patients). One (1) of these 

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patients received placebo of vitamin D (2 reported AEs). All 4 AEs (patients received 
active vitamin D) were also assessed as related to ibuprofen and/or Diamyd and all is 
reported as recovered (1 dizziness, 2 injection site reaction, and 1 common cold).  
 
Vitamin D in a dose of 2000 IU/day in children has been reported safe48. Additionally, 
a dose of up to 7000 IU/day given to children from 5 years of age with human 
immunodeficiency virus (HIV) did not raise any safety concerns49.  
 
Patients will only receive vitamin D/placebo if their screening vitamin D is below 
100 nmol/L (40 ng/ml) and the vitamin D/placebo treatment will be dismissed if the 
patient develops hypercalcemia. So, if the patient has Vitamin D serum levels above 
100 nmol/L (40 ng/ml) at screening, no Vitamin D/placebo treatment will be given to 
that patient and only Diamyd/placebo injections will be given. 
5.3 
Risks of Combining Diamyd and Vitamin D 
We would not foresee that the addition of vitamin D treatment to the Diamyd 
treatment would increase the theoretical risks of Diamyd, such as acceleration of the 
autoimmune process, undesirable effects on the immune system, or neurological 
disease.   
5.4 
Justification – Risk-Benefit 
The hypothesis is that the proposed treatment regime will rebalance islet cell 
interactions and the pancreatic immune environment to increase beta cell function and 
limit the autoimmune reaction. This will improve blood sugar control and at the same 
create a more fertile field for the GAD65 antigen specific immunotherapy Diamyd to 
induce long term tolerability. Administering Diamyd directly into lymph nodes may 
enhance the tolerizing effect even more (see rationale in section 4.3). 
 
The individual risks of Diamyd and oral vitamin D are not expected to be increased by 
combining them in the proposed manner. 
 
The justification for the proposed study with the combination treatment regimen, 
combined with the proposed exclusion and inclusion criteria and 15-months follow-up 
investigate if the combination of Diamyd and vitamin D slow down or halt the 
progress of autoimmune beta cell destruction in T1D, aiming to preserve blood 
glucose control and endogenous insulin secretion and thereby possibly reduce both 
acute and long-term complication of the disease. As Diamyd has proven to be well 
tolerated in a large number of patients in previous studies, the possibility of 
therapeutic benefit outweighs the risks. In order to safeguard the patients, a DSMB 
will review data from the study twice a year.  
 
 
 
 

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6 
TRIAL OBJECTIVES AND PURPOSE 
6.1 
Aim of Present Study 
The main goal is to find a reasonably safe and tolerable treatment for young and adult 
patients with T1D which can preserve residual insulin secretion, improve the patients’ 
quality of life (QoL) and reduce the risk of both short- and long term complications. 
6.2 
Primary Objective 
The primary objective is to evaluate the efficacy of Diamyd, administered into lymph 
nodes in combination with an oral vitamin D regimen, compared to placebo in terms 
of preserving endogenous insulin secretion as measured by C-peptide. 
6.3 
Secondary Objectives 
The secondary objectives are to compare Diamyd, administered into lymph nodes in 
combination with an oral vitamin D regimen and placebo treatment with respect to the 
effects on the diabetes status, treatment safety, immune system and quality of life 
(QoL) of the patients. 
6.4 
Endpoints 
6.4.1 
Primary Endpoint 
The primary endpoint in this study is: 
• Change in C-peptide (AUCmean 0-120 min-) during a Mixed Meal Tolerance Test 
(MMTT) between baseline and 15 months. 
 
6.4.2 
Secondary Endpoints 
The key secondary endpoints to evaluate diabetic status are: 
• Change in insulin-dose-adjusted HbA1c (IDAA1c) between baseline and 15 
months. 
• 
Change in HbA1c between baseline and 15 months. 
• Change in daily exogenous insulin consumption between baseline and 15 
months. 
 
The other secondary endpoints to evaluate diabetic status are: 
• Change in glycemic variability/fluctuations (evaluated from data from 
continuous glucose monitoring FreeStyle LibrePro, Flash Glucose Monitoring 
[FGM]) over 14 day period between Screening and 15 months. 
• Proportion of patients with IDAA1c ≤ 9 at 15 months. 
• Proportion of patients with a stimulated maximum C-peptide level above 
0.2 nmol/L (0.6 ng/ml) at 15 months. 
• Proportion of patients with a stimulated 90min C-peptide level above 
0.2 nmol/L (0.6 ng/ml) at 15 months. 
• Number of self-reported episodes of severe hypoglycemia (Severe 
hypoglycemia defined as needing help from others and/or seizures and/or 
unconscious) between baseline and 15 months. 
• Change in Rate of hypoglycemic events between baseline and 15 months. 

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• Number of patients having at least 1 severe hypoglycemic event between 
baseline and 15 months. 
• Change in maximum C-peptide during MMTT between baseline and 
15 months. 
• Change in Fasting C-peptide between baseline and 15 months. 
• C-peptide measured at 30, 60, 90, and 120 minutes during MMTT at 
15 months. 
• Change in body weight and body mass index (BMI) between baseline and 15 
months 
 
 
The secondary endpoints to evaluate safety are: 
• Injection site reactions 
• Occurrence of AEs 
• Laboratory measurements (hematology and clinical chemistry) 
• Urine analysis (microalbuminuria, creatinine) 
• Physical examinations, including neurological assessments 
• GAD65A titer  
• Vital signs (blood pressure [BP]) 
 
The secondary endpoints to evaluate the influence on the immune system are: 
• Concentrations of serum autoantibodies towards GAD65 and IA-2. 
• Concentrations of serum autoantibody isotypes towards GAD65. 
• Secretion of cytokines interleukin (IL)-1, IL-2, IL-5, IL-13, IL-10, IL-17, 
interferon (IFN)γ, and tumour necrosis factor (TNF)α by peripheral blood 
mononuclear cells (PBMCs) upon stimulation with GAD65. 
• Serum concentrations of cytokines IL-1, IL-2, IL-5, IL-13, IL-10, IL-17, IFNγ, 
and TNFα. 
• Secretion of cytokines IL-1, IL-2, IL-5, IL-13, IL-10, IL-17, IFNγ, and TNFα 
by PBMCs upon stimulation with anti-CD3 and anti-CD28. 
• Proliferation of PBMCs upon stimulation with GAD65. 
• Further exploratory immunological characterization. 
 
The secondary endpoints of Quality of Life are: 
• Change in QoL as measured by questionnaire EQ-5D-5L between baseline and 
Month 15. 
• Quality adjusted life years (QALYs) based on the EQ-5D-5L questionnaire. 
 
6.4.3 
Exploratory Endpoints 
All data collected at the 24-month follow-up visit (Visit  8) will be regarded as 
exploratory endpoints and will be presented using summary statistics including data 
from the main study period where only the patients that participated in the Extended 
Study Period will be included. The following statistical analyses will be repeated for 
the whole study period:  
 
• The change in log-transformed C-peptide AUCmean 0-120 min during an 
MMTT from baseline to Month 24 

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• Change in HbA1c between baseline and 24 months 
• Change in daily exogenous insulin consumption between baseline and 
24 months 
• Change in Fasting C-peptide between baseline and 24 months. 
• Change in glycemic variability/fluctuations (evaluated from data from 
continuous glucose monitoring FreeStyle LibrePro, FGM) over 14 day 
period between Screening and 24 months. 
• Rate of hypoglycemic events using Poisson regression including 
randomization strata (GAD65A) 
• Number of patients having at least 1 severe hypoglycemic event using 
Cochran/Mantel-Haenszel Test stratified for randomization strata 
(GAD65A) 
• Change in body weight and body mass index (BMI) between baseline and 
24 months 
 
 

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7 
TRIAL DESIGN 
7.1 
Description of the Study Design and Procedures 
The study is a 2-arm, randomized, double-blind, placebo-controlled study in GAD65A 
positive T1D patients aged ≥12 and <25 years old, diagnosed within 6 months prior to 
screening with fasting C-peptide levels ≥0.12 nmol/L (0.36 ng/ml). In total, the aim is 
to recruit 106 patients at approximately 22 sites. The patients will be followed for 15 
months with 7 visits to the clinic (Table 2) in the Main Study Period. All patients that 
are ongoing, i.e. have not performed Visit 7 (Month 15) when protocol version 7 is 
approved and implemented, will be asked to participate in the Extension Study Period 
which include Visit 8 at month 24 (Table 3). 
 
Patients and parent(s)/guardian(s), as applicable, will provide written informed 
consent before any study-related procedures are performed. On Day 1 (Visit 2), 
2-4 weeks after the Screening Visit, patients eligible for the study will be randomized 
in a 1:1 ratio stratified by GAD65A level and country to receive either: 
• i) three (3) intralymphatic injections with 4 µg Diamyd on Days 30, 60, and 90 
and; ii) oral vitamin D 2000 IE daily for 4 months (from Day 1 through 
Day 120) 
• i) three (3) intralymphatic injections of Placebo for Diamyd on Days 30, 60, 
and 90 and; ii) oral Placebo for vitamin D daily for 4 months (from Day 1 
through Day 120) 
The treatment schedule is given in Table 1. 
 
At the screening visit patients will be assigned a 3-digit country/site number and a 
3-digit sequential screening number and these numbers together will be used as a 
6-digit patient identification (Patient Number), i.e. XXX-YYY. 
 
Individual patients will be exposed to Diamyd for a maximum of 3 months and 
vitamin D for a maximum of 4 months. All patients will continue to receive intensive 
insulin treatment from their personal physicians during the whole study period. All 
patients will be monitored for at least 1 hour after administration of each 
Diamyd/placebo injection. 
 
When the last patient has completed the double-blind study period, the study code will 
be broken and results analyzed.  
 
 
 

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Abbreviations: AEs=Adverse Events; BP= Blood Pressure; eDiary=electronic Diary; 
GAD65A=Antibodies to glutamic acid decarboxylase with molecular mass 65kDa; 
HBA1c=Hemoglobin A1c; HLA=Histocompatibility antigen; MMTT=mixed meal tolerance test; 
FGM=Flash Glucose Monitoring; GAD65=Glutamine acid decarboxylase with a molecular mass of 
65kDa; GAD65A= antibodies to GAD65; MMTT=Mixed Meal Tolerance Test; T1D=Type 1 Diabetes; 
QoL=Quality of Life 
 
a. 
Study drug administration: For Visit 4 and 5 the visit date must be set in accordance with Visit 3 and 4, respectively, 
so that the first, second and third doses will be 30 days apart (± 5days). 
b. 
If the fasting c-peptide concentration is not ≥0,12 nmol/L (0.36 ng/ml) at the screening visit this test can be repeated 
on another day within a period of 2 weeks (maximum 2 tests on different days within a 2-week period).  
c. 
The Diamyd/placebo injection directly into the inguinal lymph node is to be done by an appropriately qualified person 
at the X-ray department by help of ultrasound technique. For more information regarding the injection please refer to 
the operations manual for the injection procedure. 
d. 
Treatment with vitamin D/placebo starts at Visit 2 if the Vitamin D serum levels are below 100 nmol/L (40 ng/ml) at 
screening. If the patient has Vitamin D serum levels above 100 nmol/L (40 ng/ml) at screening, no Vitamin D/placebo 
treatment will be given for that patient.  
e. 
General Physical Exam also to include height and weight 
f. 
Pubertal Stage should be measured when applicable. Not applicable >1 5 years after the patient have reached final 
height 
g. 
The investigator/study nurse will inspect the injection site before and after the injection is given and record any 
injection site reactions in the electronic Case Report Form (eCRF) 
h. 
The patient will record injection site reactions in the eDiary starting the day after injection and for 7 days following 
the injection. Injection site reactions reported by patients in the eDiary during day 1-7 following an injection should 
not be reported as an AE in the eCRF. Any injections site reactions reported after the 1 week recording period will be 
recorded as AEs in the eCRF. 
i. 
Patients will record insulin dose in the eDiary for 4 days prior each visit starting from Visit 2. Insulin dose collected at 
Visit 2 (for the 4 days prior to Visit 2) will be done by the Investigator and recorded in the eCRF.  
j. 
FGM during 2 weeks post visit for Visits 1, 6 and 7. Patients will be given instructions on when and where to return 
the device after the testing period. For instruction on how to return the Freestyle Libre Pro sensor, please refer to the 
Freestyle Libre Pro Worksheet. 
k. 
The number of self-reported severe hypoglycemia (defined as needing help from others and/or seizures and/or 
unconsciousness) should be recorded in the eCRF and each event will be recorded separately. 
l. 
See Procedure for MMTT in the Operations Manual 
m. 
Only applicable to patients completing their Visit 7 after 01 January 2020. 
n. 
Patients that have completely withdrawn from the study will be asked to return for a final visit at month 15, in order to 
achieve as complete as possible follow-up. See section 8.5 for further details.  
 
 
 

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f. 
See Procedure for MMTT in the Operations Manual 
g. 
Patients that are ongoing, i e. have not performed Visit 7 (Month 15) when protocol version 7 is approved and 
implemented, will be asked to consent for the Extension Study Period an additional visit at Month 24. 
 
7.1.1 
Study Procedures 
The study procedures and assessments are described in the section below and 
presented in detail in Section 9.1 (diabetes status assessments), Section 9.2 (safety), 
Section 9.3 (immunological assessments), Section 9.4 (genetic status assessments), 
Section 9.5 (vitamin D status), Section 9.7 (Quality of Life) Section 9.7 (pubertal 
stage, concomitant medication assessments), and Section 9.9 (demographics). 
Recording and reporting of AEs are described in detail in Section 11. 
The timing of all study events is shown in Table 2 and Table 3 in Section 7.1. 
 
7.1.1.1 All Visits, Visit 1 through Visit 8 
Note that the patient should attend all study visits in the morning following an 
overnight fast (>10 hours, water allowed). For patients with evidence of an infection 
(including fever), the complete visit should be postponed for 5 days or until the 
patient has recovered. 
 
7.1.1.2 Timing of all visits, Visit 1 through Visit 8 
The first visit, the screening visit (Visit 1) should be performed 14 to 28 days before 
planned Visit 2 (Baseline), when Vitamin D treatment starts. One month (30 days) 
later, at Visit 3, the first injection of Diamyd will be administered. For Visit 4 (second 
Diamyd administration), the visit date must be set in accordance with Visit 3 (i.e. the 
first Diamyd administration) so that the first and second Diamyd doses will be 
30 days apart (±5 days). For Visit 5 (third Diamyd administration) the visit date must 
be set in accordance with Visit 4 (i.e. the second Diamyd administration) so that the 
second and third Diamyd doses will be 30 days apart (± 5 days). For Visit 6, 7 and 8, 
the visit date must be calculated from baseline (Visit 2) ±14 days. 
 
 
7.1.1.3 Visit 1, Screening (Day -14 to -28) 
The screening examination will take place within 6 months of diagnosis of T1D. 
Potential study patients and guardian(s), where applicable, will receive both written 
and oral information about the study procedures, potential risks, and benefits. Before 
any study specific procedures may be performed, the patients and guardian(s), where 
applicable, must sign the informed consent form (ICF). After written informed 
consent has been obtained, the following activities and assessments will be 
performed: 
• Eligibility will be checked versus the inclusion/exclusion criteria 
• Demographics (including age and gender) 
• Medical history 
• Family history of T1D 
• General Physical Examination, including weight and height 
• Neurological Assessment 
• Concomitant medication 
• Vital signs (BP) 
• Pubertal stage, if applicable 

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• Glycemic variability/fluctuations device (FreeStyle LibrePro, FGM) will be 
given to the patient 
• Urine pregnancy test (menarchal females only) 
• Blood sampling for hematology, clinical chemistry and GAD65A 
• Blood sampling for vitamin D status 
• Urine analysis for microalbuminuria and creatinine 
• Blood samples for diabetes status (fasting C-peptide, HbA1c and fasting 
glucose) 
• The patient will be instructed to collect the insulin dose 4 days prior to the 
next visit and the site will send text message/call to remind the patient 
If the fasting c-peptide concentration is not ≥0,12 nmol/L (0.36 ng/ml) at the 
screening visit this test can be repeated on another day within a period of 2 weeks 
(maximum 2 tests on different days within a 2-week period). 
 
Examinations will be performed according to Table 2, and in the order outlined in the 
electronic case report form (eCRF). 
 
7.1.1.4 Visit 2, Baseline (Day 1) 
At Visit 2 (baseline) the following activities and assessments will be performed: 
• Eligibility will be checked versus the inclusion/exclusion criteria 
• Randomization in Interactive Web Response System (IWRS) 
• Start of treatment with the oral treatment of vitamin D/Placebo (if the Vitamin 
D serum levels are below 100 nmol/L [40 ng/ml] at screening) 
• General Physical Examination, including weight and height 
• Neurological Assessment 
• Concomitant medication 
• Vital signs (BP) 
• Insulin dose collected (Exogenous insulin dose/kg/24 hours) for 4 days prior 
to visit 
• AEs 
• Urine pregnancy test (menarchal females only) 
• Self-reported severe hypoglycemia (defined as needing help from others 
and/or seizures and/or unconsciousness) 
• QoL questionnaire 
• MMTT 
• Blood sampling for hematology, clinical chemistry and GAD65A 
• Blood sampling for other immunological parameters 
• Blood sampling for vitamin D status 
• Urine analysis for microalbuminuria and creatinine 
• Blood samples for diabetes status (fasting C-peptide, MMTT-induced 
C-peptide, HbA1c, fasting glucose and MMTT-induced glucose) 
• Electronic Diary (eDiary) activated and patients trained in how to use it 
Examinations will be performed according to Table 2, and in the order outlined in the 
eCRF. 
 
7.1.1.5 Visit 3, Month 1 (Day 30 ±5) 
At Visit 3 (Month 1) the following activities and assessments will be performed: 

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• Treatment with Diamyd/Placebo injection  
• Injection site inspection by the Investigator/Study Nurse 
• Patient instructed on how to record injection site injections in the eDiary 
• General Physical Examination, including weight and height 
• Neurological Assessment 
• Concomitant medication 
• Vital signs 
• AEs 
• Urine pregnancy test (menarchal females only) 
• Self-reported severe hypoglycemia (defined as needing help from others 
and/or seizures and/or unconsciousness)  
• Blood sampling for hematology, clinical chemistry, GAD65A and HLA 
characterization 
• Blood sampling for other immunological parameters 
• Blood sampling for vitamin D status 
• Urine analysis for microalbuminuria and creatinine 
• Blood samples for diabetes status (fasting C-peptide, HbA1c and fasting 
glucose) 
• Check of eDiary use compliance 
 
Examinations will be performed according to Table 2, and in the order outlined in the 
eCRF. 
 
7.1.1.6 Visit 4, Month 2 (Day 60 ±5) and Visit 5, Month 3 (Day 90 ±5) 
For Visit 4 and 5 the visit date must be set in accordance with Visit 3 and 4, 
respectively, so that the first, second and third doses will be 30 days apart (± 5days). 
 
At Visit 4 (Month 2) and Visit 5 (Month 3) the following activities and assessments 
will be performed: 
• Treatment with Diamyd/Placebo injection  
• Injection site inspection by the Investigator/Study Nurse and check for patient 
reported injection site recordings for previous visit in eDiary 
• General Physical Examination, including weight and height 
• Neurological Assessment 
• Concomitant medication 
• Vital signs (BP) 
• AEs 
• Urine pregnancy test (menarchal females only) 
• Self-reported severe hypoglycemia (defined as needing help from others 
and/or seizures and/or unconsciousness) 
• Blood sampling for hematology, clinical chemistry and GAD65A  
• Blood sampling for other immunological parameters 
• Blood sampling for vitamin D status 
• Urine analysis for microalbuminuria and creatinine 
• Blood samples for diabetes status (fasting C-peptide, HbA1c and fasting 
glucose) 
• Check of eDiary use compliance 

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• Confirm with the patient that last dose of vitamin D/placebo will occur at 
month 4 (before next visit month 6) 
Examinations will be performed according to Table 2, and in the order outlined in the 
eCRF. 
 
7.1.1.7 Visit 6, Month 6 (Day 180 ±14) 
At Visit 6 (Month 6) the following activities and assessments will be performed: 
• General Physical Examination, including weight and height 
• Neurological Assessment 
• Concomitant medication 
• Vital signs 
• Pubertal stage, if applicable 
• Glycemic variability/fluctuations device (FreeStyle LibrePro, FGM) will be 
given to the patient 
• AEs 
• Urine pregnancy test (menarchal females only) 
• Self-reported severe hypoglycemia (defined as needing help from others 
and/or seizures and/or unconsciousness) 
• QoL questionnaire 
• MMTT 
• Blood sampling for hematology, clinical chemistry and GAD65A 
• Blood sampling for other immunological parameters 
• Blood sampling for vitamin D status 
• Urine analysis for microalbuminuria and creatinine 
• Blood samples for diabetes status (fasting C-peptide, MMTT-induced C-
peptide, HbA1c, fasting glucose, and MMTT-induced glucose) 
• Check of eDiary use compliance 
• Collection of used and unused vitamin D/placebo for accountability 
Examinations will be performed according to Table 2, and in the order outlined in the 
eCRF. 
 
7.1.1.8 Visit 7, Month 15 (Day 450 ±14) 
At Visit 7 (Month 15) the following activities and assessments will be performed: 
• General Physical Examination, including weight and height 
• Neurological Assessment 
• Concomitant medication 
• Vital signs 
• Pubertal stage, if applicable 
• Glycemic variability/fluctuations device (FreeStyle LibrePro, FGM) will be 
given to the patient 
• AEs 
• Urine pregnancy test (menarchal females only) 
• Self-reported severe hypoglycemia (defined as needing help from others 
and/or seizures and/or unconsciousness) 
• QoL questionnaire 
• MMTT 
• Blood sampling for hematology, clinical chemistry and GAD65A 

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• Blood sampling for other immunological parameters 
• Blood sampling for vitamin D status 
• Urine analysis for microalbuminuria and creatinine  
• Blood samples for diabetes status (fasting C-peptide, MMTT-induced C-
peptide, HbA1c, fasting glucose and MMTT-induced glucose) 
• Serological test for Covid-19 (for patients completing their Visit 7 after 01 
January 2020) 
• Check of eDiary use compliance and inactivate the account (only applicable 
for patients that are not continuing in the Extension Study Period) 
 
Examinations will be performed according to Table 2, and in the order outlined in the 
eCRF. 
 
7.1.1.9 Visit 8, Month 24 (Day 720 ±14) 
Visit 8 will only be performed by patients that are ongoing i.e. have not performed 
Visit 7 (Month 15) when protocol version 7 is approved, implemented and gives their 
consent to enter the Extension Study Period. Study patients and guardian(s), where 
applicable, will be asked to sign the updated ICF describing Visit 8 (Extension Study 
Period).  
At Visit 8 (Month 24) the following activities and assessments will be performed: 
• General Physical Examination, including weight and height 
• Neurological Assessment 
• Concomitant medication 
• Vital signs 
• Pubertal stage, if applicable 
• Glycemic variability/fluctuations device (FreeStyle LibrePro, FGM) will be 
given to the patient 
• AEs 
• Urine pregnancy test (menarchal females only) 
• Self-reported severe hypoglycemia (defined as needing help from others 
and/or seizures and/or unconsciousness) 
• QoL questionnaire 
• MMTT 
• Blood sampling for hematology, clinical chemistry and GAD65A 
• Blood sampling for other immunological parameters 
• Blood sampling for vitamin D status 
• Urine analysis for microalbuminuria and creatinine  
• Blood samples for diabetes status (fasting C-peptide, MMTT-induced C-
peptide, HbA1c, fasting glucose and MMTT-induced glucose) 
• Serological test for Covid-19  
• Check of eDiary use compliance and inactivate the account  
 
Examinations will be performed according to Table 3, and in the order outlined in the 
eCRF. 

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7.2 
Patient Diary 
The patients will be supplied with an eDiary at Visit 2. The diary will be internet 
based and the patients will be able to access the diary from either a computer or a 
smart phone. From Visit 3 until Visit 8 the patient will record insulin doses 4 days 
before each visit (at Visit 2 the insulin dose will be collected at the visit and will be 
done by the Investigator and recorded in the eCRF). The patient will also use the 
eDiary for documentation of injection site reactions during the week following 
injection (Visits 3, 4 and 5), starting the day after the injection.   
 
The patient will be carefully instructed by study personnel on how to log in and 
complete the eDiary. The investigator/study nurse will review the eDiaries at each 
visit to check that the patient is completing the eDiary as instructed. Injection site 
reactions reported by patients in the eDiary during day 1-7 following an injection 
should not be reported as AEs in the eCRF. 
7.3 
Study Stopping Criteria 
The Sponsor and the investigators reserve the right to discontinue the study at any 
time for safety reasons or other reasons jeopardizing the justification of the study. 
Such a termination will be implemented in a time frame that is compatible with the 
patient’s wellbeing.   
 
If the study is prematurely terminated or suspended, the investigator should promptly 
inform the patients and assure appropriate therapy and follow-up. The Sponsor will 
notify the Regulatory Authorities and the Independent Ethics Committees (IECs) of 
any plans to terminate the study. 
7.4 
Decision Criteria 
A patient is included in the study when the ICF has been signed at the screening visit 
(Visit 1). No patients will be enrolled until approvals from the appropriate IECs and 
Regulatory Authorities have been obtained.   
 
Prior to the study starting, it will be confirmed that all regulatory requirements for 
starting the study are met. All key documents must be on file in the Sponsor and 
Investigator’s File, respectively. 
7.5 
Management of the Disease 
All patients will continue to receive intensive insulin treatment through their personal 
physicians via multiple daily injections of insulin or via insulin pump and should not 
use any oral or injected non-insulin pharmaceuticals for glycemic control. If, by 
mistake, such medication is introduced during the study, this is not a reason for 
discontinuation of the patient. The primary responsibility for diabetes management 
will be the treating or referring diabetes care provider, but the research study team 
will provide close additional support through interaction by phone as needed. 
Diabetes management will be monitored by the study staff with phone calls between 
study visits as needed. Patients will fill in their insulin doses 4 days before each visit 
in the patient diary. 
 

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The following diabetes treatment goals will be given to patients and treating 
physicians in accordance with the current recommendations of the American Diabetes 
Association (ADA) 27 
• Pre-meal glucose 4.4 to 7.2 mmol/L 
• Bedtime/overnight glucose 5 to 8.3 mmol/L 
• HbA1c <53 mmol/mol (Diabetes Control and Complications Trial 
[DCCT]-aligned)  
These goals are only for guidance and are not considered as violating the protocol if 
not achieved, but it is regarded as important that every patient and treating physician 
make their best effort to achieve these recommendations. 
 
The investigator/diabetes team/study nurse will provide support for T1D management 
by making scheduled phone calls to patients if HbA1c results are ≥53 mmol/mol at 
any study visit.   
7.6 
Data Safety Monitoring Board 
An independent DSMB will be appointed. The DSMB will review the safety data 
throughout the study period twice a year. A DSMB charter will be written to outline 
the working procedures and the duties of the DSMB.  
 
 

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8 
STUDY POPULATION 
Approximately 22 sites in Sweden, Spain, Czech Republic and the Netherlands will 
include up to 106 patients. T1D patients, diagnosed within 6 months are given 
information about the study and they (and their guardian(s) if applicable) are asked to 
participate in the trial.  
8.1 
Inclusion Criteria 
1. Informed consent given by patients and/or patient’s parent(s) or legal 
acceptable representative(s) (guardian(s)) according to national regulations 
2. T1D according to the ADA classification diagnosed ≤6 months at the time of 
screening  
3. Age: ≥12 and <25 years old 
4. Fasting C-peptide ≥0.12 nmol/L (0.36 ng/ml) on at least one occasion 
(maximum 2 tests on different days within a period of 2 weeks) 
5. Positive for GAD65A but < 50 000 IU/ml 
6. Females must agree to avoid pregnancy and have a negative urine pregnancy 
test. 
Patients of childbearing potential must agree to use adequate contraception, 
until one (1) year after the last administration of Diamyd. Adequate 
contraception is as follows:  
For females of childbearing potential: 
a. oral (except low‐dose gestagen (lynestrenol and norestisteron)), 
injectable, or implanted hormonal contraceptives 
b. combined (estrogen and progestogen containing)  
c. oral, intravaginal or transdermal progesterone hormonal 
contraception associated with inhibition of ovulation  
d. intrauterine device 
e. intrauterine hormone-releasing system (for example, progestin‐
releasing coil) 
f. bilateral tubal occlusion 
g. vasectomized male (with appropriate post vasectomy 
documentation of the absence of sperm in the ejaculate) 
h. male partner using condom 
i. abstinence from heterosexual intercourse  
 
For males of childbearing potential: 
a. condom (male) 
b.  abstinence from heterosexual intercourse 
8.2 
Exclusion Criteria 
1. Previous or current treatment with immunosuppressant therapy (although 
topical or inhaled steroids are accepted) 
2. Continuous treatment with anti-inflammatory drug (sporadic treatment e.g. 
because of headache or in connection with fever a few days will be accepted) 
3. Treatment with any oral or injected anti-diabetic medications other than 
insulin 
4. Treatment with Vitamin D, marketed or not, or unwilling to abstain from such 
medication during the trial 

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5. A history of anemia or significantly abnormal hematology results at screening 
6. A history of epilepsy, head trauma or cerebrovascular accident, or clinical 
features of continuous motor unit activity in proximal muscles 
7. Clinically significant history of acute reaction to vaccines or other drugs in the 
past 
8. Treatment with any vaccine, including influenza vaccine, within 4 months 
prior to planned first study drug dose or planned treatment with any vaccine up 
to 4 months after the last injection with study drug. 
9. Participation in other clinical trials with a new chemical entity within the 
previous 3 months 
10. Inability or unwillingness to comply with the provisions of this protocol 
11. A history of alcohol or drug abuse 
12. A significant illness other than diabetes within 2 weeks prior to first dosing 
13. Known HIV or hepatitis 
14. Females who are lactating or pregnant (the possibility of pregnancy must be 
excluded by urine βHCG on-site within 24 hours prior to the Diamyd/placebo 
treatment) 
15. Presence of associated serious disease or condition, including active skin 
infections that preclude intralymphatic injection, which in the opinion of the 
investigator makes the patient non-eligible for the study 
16. Deemed by the investigator not being able to follow instructions and/or follow 
the study protocol 
8.3 
Recruitment and Screening 
Eligible patients and/or their parent(s)/legal guardian(s) will have the study explained 
to them, and will receive the written patient information. After having had the time to 
review the nature of the study, they will have the opportunity to ask questions to the 
investigational team. If, after this, the patients agree to participate, they will personally 
sign and date the written ICF. Patients and/or their parent(s)/legal guardian(s) will 
provide written informed consent before any study-related procedures are performed.   
 
The patients and/or their parent(s)/legal guardian(s) will then receive a copy of the 
signed and dated patient information/ICF. 
8.4 
Patient Withdrawal Criteria 
The patient and the parent(s) / legal guardian(s) (where applicable) will receive oral 
and written information about the study, which includes information about the right to 
withdraw from the trial at any time without prejudice to future treatment. In addition, 
the patient may be withdrawn at the investigator’s or Sponsor’s discretion at any time 
if regarded in the patient’s best interest. In the event that the patient drops out of the 
trial or is withdrawn from the trial, the appropriate withdrawal page (Study 
Termination Report) in the eCRF must be completed. Please note that a Study 
Termination Report must be completed for all patients who have given informed 
consent and who have been assigned a patient number. 
 
Reasonable efforts should be made to contact any patient lost to follow-up during the 
course of the trial in order to complete assessments and retrieve any outstanding data.   
 
Patients withdrawn after randomization will not be replaced. 
 

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Note that any changes in insulin requirement are not a reason for withdrawal of the 
patient from the study. 
8.5 
Patient Withdrawal 
In accordance with the Declaration of Helsinki, the investigator must explain to the 
patient that they have the right to withdraw from the study at any time, and that this 
will in no way prejudice their future treatment. The reason for any kind of withdrawal 
must be recorded on the appropriate section of the eCRF. 
 
There will be two main categories for withdrawals from the study: 
 
Complete withdrawal (i.e. stopping investigational product(s) and also continued 
efficacy and safety evaluations). In order to achieve as complete as possible 15 month 
follow-up, whenever feasible, patients that are considered for complete withdrawal 
should be asked if they could consider to return for a 15-month visit, preferable 
complete visit but as a minimum do the MMTT, C-peptide and HbA1c sampling, and 
collection of AEs. Attempts should be made to contact patients lost to follow-up with 
respect to this.  
 
Standard reasons for withdrawing from further participation in the study and from the 
follow-up visits may be: 
• Patient’s decision (withdrawal of consent to participate) 
• Patient lost to follow-up  
 
Withdrawals from investigational product(s) (i.e. stopping one or several 
investigational products, but continuing follow-up visits, including efficacy and safety 
evaluations) 
 
Standard reasons from withdrawing from taking further investigational product, but 
continuing follow-up visits and safety evaluations may be: 
 
• Unacceptable AEs 
• Patient request 
• Investigator's discretion 
• Patient lost to follow-up/non-attendance 
• Intercurrent illness 
• The patient becomes pregnant 
 
Diamyd/placebo should not be given to the patient if the patient after inclusion in the 
study develops/experiences:  
- 
Brain damage, epilepsy, head trauma, neurological disease 
- 
Any active, serious hormonal disease other than T1D 
- 
Other severe autoimmune disease (except celiac disease which is accepted for 
inclusion) 
- 
Immune-suppressive treatment 
- 
Cancer, cancer treatment 
- 
Any other diabetes drugs other than insulin (and the combination regimen 
administered in this study) 
- 
Any vaccination  

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- 
Drug/alcohol abuse 
- 
Becomes pregnant or is no longer willing to use safe contraceptives during the 
study 
 
Vitamin D/placebo treatment should not be continued if the patient after inclusion in 
the study develops/experiences: 
- 
Symptoms of hypercalcemia such as tiredness, euphoria, drowsiness, nausea, 
weight loss, thirst, polyuria, nefrocalcinosis, renal failure  
- 
Arrhythmia  
- 
Pancreatitis 
 
However, whenever a patient is withdrawn from a study, or for whatever reason is not 
coming to any further visits, a final study evaluation must be completed for that patient 
stating the reason(s) why the patient was withdrawn from the study. All documentation 
concerning the patient must be as complete as possible. 
 
Withdrawals due to non-attendance must be followed up by the investigator to obtain 
the reason for non-attendance. Withdrawals due to intercurrent illnesses or AEs must 
be fully documented in the eCRF, with the addition of supplementary information if 
available and/or appropriate. 
 
 
 

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9 
STUDY ASSESSMENTS 
9.1 
Assessment of Variables of Diabetes Status 
9.1.1 
Mixed Meal Tolerance Test 
Meal stimulated glucose and C-peptide will be assessed using the MMTT.  
The MMTT must be performed according to the instructions in the Operations 
Manual. 
The timing of the assessments is described in Section 7.1.1 and Table 2 and Table 3. 
The patient should: 
• Come to the study site following an overnight fast (>10 hours), i.e. the patient 
may not eat but is permitted to drink water  
• Not take short acting/direct acting insulin within 6 hours before the MMTT. 
The patient is allowed to take base-insulin day/night before, but not in the 
morning before the MMTT.  
• Patients with CSII (insulin pump) must continue with their basal dose insulin, 
but not add bolus dose during the last 6 hours before the MMTT 
• Have a fasting plasma glucose level in the range defined by 4-12 mmol/L on 
the patient’s home blood glucose meter in the morning of the test  
 
If the patient does not fulfill all of the above criteria, the MMTT should be 
rescheduled and the patient should return to the study site within 5 days if possible. 
 
If a patient has a blood sugar level <4 mmol/L in the morning of the scheduled visit, 
the patient is allowed to take dextrose tablets and then come to the study site. The 
patient is allowed to perform the MMTT if the blood sugar level is >4 mmol/L when 
the patients arrive at the study site. If the blood sugar level is still <4 mmol/L the visit 
should be rescheduled according to the instructions below.  
 
For patients with clinical signs of ketoacidosis or unequivocal elevation of fasting 
plasma glucose (>12 mmol/L [216 mg/dl]) on the patient’s home blood glucose meter, 
the complete visit should be postponed and the patient should return to the study site 
within 5 days of the scheduled visit. Please note that all study 
procedures/examinations must be postponed. 
 
If for safety reasons, patients need to eat or take insulin, the visit should also be 
rescheduled. 
9.1.2 
Hemoglobin A1c 
Blood samples will be taken to measure HbA1c levels and will be analyzed at a 
central laboratory, 
The timing of the assessments is 
described in Section 7.1.1 and Table 2 and Table 3. 
9.1.3 
Fasting Glucose and Fasting C-Peptide 
Blood samples will be taken to measure fasting glucose and fasting C-peptide levels 
and will be analyzed at 
The timing of the assessments is described in Section 
7.1.1 and Table 2 and Table 3. 

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9.1.4 
Glycemic Fluctuations/Variability 
The FreeStyle Libre Pro FGM System is a professional continuous glucose 
monitoring (CGM) device indicated for detecting trends and tracking patterns and 
glucose level excursions above or below the desired range, facilitating therapy 
adjustments in persons with diabetes. Readings from the FreeStyle Libre Pro FGM 
System are not made available directly to patients in real time. The FreeStyle Libre 
Pro FGM System aids in the detection of episodes of hyperglycemia and 
hypoglycemia, facilitating therapy adjustments. 
 
Patients will be instructed to return the FreeStyle to the site after each of the testing 
periods following Visit 1,6, 7 and 8. For instruction on how to return the Freestyle 
Libre Pro sensor, please refer to the Freestyle Libre Pro Worksheet. The timing of the 
distribution of the glucose monitoring system and assessments is described in Section 
7.1.1 and Table 2 and Table 3. 
9.2 
 Assessment of Safety Variables 
The safety assessments include:  
• 
Reactions at the injection site 
• 
Occurrence of AEs 
• 
Laboratory measurements (hematology and clinical chemistry) 
• 
Urine analysis  
• 
Physical examinations, including neurological assessments 
• 
GAD65A titer  
• 
Vital signs 
9.2.1 
Adverse Events  
AEs will be recorded throughout the study period from Visit 2 (baseline) to 
completion of Visit 8. Events occurring until the day before first administration of 
investigational medicinal product (IMP) (Visit 2) will be recorded as medical history 
and as AEs from start of first administration of IMP (day of Visit 2 and onwards). 
 
SAE will be recorded from signing ICF. 
 
AEs will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA). 
For further information of definitions and reporting of AEs and SAEs and Incidents, 
see Section 11. 
 
9.2.1.1 Injection Site Reactions 
After each Diamyd/Placebo injection, the injection sites will be inspected by the 
Investigator/Study Nurse and reactions recorded in the eCRF. Patients will also 
inspect the injection site and record their observations in the patient eDiary, see 
Section 7.2. 
9.2.2 
Physical Examination 
All patients will undergo a general physical examination (general appearance 
including skin, mouth, throat, cardiovascular, abdomen, lymphatic glands, and 
neurological/musculoskeletal [including reflexes]). 
The timing of the assessments is described in Section 7.1 and Table 2 and Table 3. 

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The outcome of the assessments will be recorded as “normal” or “abnormal”. If the 
outcome is assessed as abnormal, the finding will be classified as “clinically 
significant” or “non-clinically significant”. 
Any findings at the screening visit (Visit 1) will be reported as pre-existing conditions 
on the Medical History eCRF page. 
 
During the subsequent study visits the patient will be examined for any new medical 
conditions or worsening of the pre-existing ones. Any change in pre-existing 
conditions or new conditions must be entered on the AE page in the eCRF and any 
medication given on the concomitant medication pages. 
9.2.3 
Neurological Examination 
All patients will undergo a standardized clinical neurological examination at all visits. 
The neurological tests are performed in order to detect possible mild signs of 
neuromuscular disease such as disturbance of strength, balance, and coordination. 
The outcome of the assessments will be recorded as “normal” or “abnormal”.  
 
The neurological examination includes:   
• Extremity reflexes 
• Romberg (balance and coordination) 
• Walk on a line, 2 meters (balance and coordination) 
• Standing on 1 leg, left and right, 15 seconds per leg (balance and coordination) 
• Finger-nose (coordination) 
• Mimic (cranial nerves) 
• Babinski reflex (central function) 
• Muscle strength (shake hands) biceps, triceps, distal extensors, and flexors 
These examinations may also be repeated between scheduled visits at the discretion of 
the investigator. Screening for neurological disease with electroencephalogram (EEG) 
is not included due to low sensitivity and specificity. However, if any signs of 
neurological dysfunction are detected, the patient should be referred to a neurologist 
for further evaluation.  
 
During the subsequent study visits the patient will be examined for any new medical 
conditions or worsening of the pre-existing ones. Any change in pre-existing 
conditions or new conditions must be entered on the AE page in the eCRF. 
9.2.4 
Vital Signs   
The following vital signs will be monitored as safety variables: 
• Supine systolic and diastolic BP (mmHg), after 5 minutes lying down 
Weight, height and BMI will also be recorded. 
 
The outcome of the assessments will be recorded as “normal” or “abnormal”. 
Abnormal findings will be assessed as “clinically significant” or “not clinically 
significant”. The timing of the assessments is described in Section 7.1 and Table 2 
and Table 3. 

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9.2.5 
Laboratory Safety Assessments  
• Hematology: (mean corpuscular hemoglobin [MCH], mean corpuscular 
volume [MCV], mean corpuscular hemoglobin concentration [MCHC], 
Hemoglobin, Platelets, Total Leukocyte Count and Differential) 
• Clinical Chemistry: Creatinine, Calcium, Liver function tests (alanine 
aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline 
Phosphatase [ALP], Bilirubin) 
• Urine analysis: Microalbuminuria Creatinine 
• Urine pregnancy tests (menarchal females only) 
The outcome of the assessments will be recorded as “normal” or “abnormal”. 
Abnormal findings (values outside the reference ranges) will be assessed as “clinically 
significant” or “not clinically significant”. 
The timing of the assessments is described in Section 7.1 and Table 2 and Table 3. 
 
The laboratory tests listed above (hematology, clinical chemistry and urine analysis) 
will be analyzed at the central laboratory 
Full details on blood sample collection, 
processing, storage, and shipping requirements (as applicable) are provided in the 
study specific Laboratory Manual. 
9.3 
Immune System Assessments 
9.3.1 
GAD65 Antibody Titer  
The timing of the assessments is described in Section 7.1 and Table 2 and Table 3. 
The variables to evaluate the influence on the immune system will be analyzed at 
 
9.3.2 
Bioanalytical Method  
Assessment of serum autoantibodies 
The quantification of serum autoantibodies towards GAD65 and IA-2, as well as 
antibody isotypes, will be performed with standard techniques. The levels of 
GAD65A indicate the general effect of the vaccine. The relative concentrations of 
GAD65A immunoglobulin G (IgG) subtypes indicate diverging effects on the 
immune reaction, and e.g. a rise in IgG4 is associated with positive effects of allergy 
immunotherapy. 
 
Assessment of antigen specifically stimulated cytokine levels 
Changes induced by immune modulation are studied with a broad range of cytokines 
involved in the regulation of the immune system. At minimum a set including IL-1, 
IL-2, IL-5, IL-13, IL-10, IL-17, IFN-γ, and TNF-α will be monitored to assess general 
and antigen specific immune responses over time. Luminex 200 will be used. 
 
Assessment of immune response to antigen by cell proliferation 
Proliferation of PBMCs is used to indicate changes in total immune response to 
autoantigens. Incorporation of 3H thymidine will be used, and provides an estimate of 
cell proliferation by measuring deoxyribose nucleic acid (DNA) synthesis. It is a 
robust technique for assessment of responses to various stimuli. 
 
Assessment of immune cell frequency 
Flow cytometric analysis allows the quantification of specific immune based on the 
presence of biomarkers before and after proliferation and activation by specific 

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antigens, and indicates changes to the immune response. It can be done by fluorescent 
activation or CyTOF based detection cells and the monitoring of changes over time. 
Enzyme Linked Immunosorbent Spot Forming Cell Assay (ELISPOT) analysis allows 
the measurement of the number of cells secreting specific cytokines upon stimulation 
with antigen (GAD65). 
 
Assessment of cell mediated immune response 
To monitor potentially favorable changes in the immune response to GAD65 and 
changes in the quality of the immune response post treatment versus baseline certain 
effects will be analyzed. A potential important biomarker is the increase of the antigen 
specific secretion of regulatory cytokine IL-10, or the Th2 cytokines IL-5 and IL-13. 
Another potential biomarker is the decrease in antigen specific secretion of the 
proinflammatory cytokines IL-17, IFN-γ, and TNF-α, or the proportion of Th2 
cytokines compared to Th1 cytokines. A potential marker is also the frequency of IL-
10 secreting cells, or a change in a certain cellular subtype as characterized by flow 
cytometry. Further compound analysis will be done in order to detect and evaluate 
other potentially important biomarkers. 
9.4 
Assessment of Genetic Status 
All patients will undergo testing for HLA determination to assess the presence of 
genes related to diabetes development. Blood samples will be taken for HLA 
determination and will be analyzed a
 
The timing of the assessments is described in Section 7.1 and Table 2 and Table 3. 
9.5 
Measurement of Vitamin D Status 
Blood samples will be taken to measure serum Vitamin D levels and will be analyzed 
at 
 The timing of the assessments is described in Section 7.1 and Table 2 and 
Table 3. Only analysis results from screening visit will be reported to investigational 
sites to confirm eligibility and need to assign to Vitamin D /Placebo treatment. This 
information will be collected and maintained at the laboratory until after database lock 
of the Main Study Period. 
9.5.1 
Blood Sampling Procedures 
Blood samples for assessments of diabetes status, laboratory safety assessments, 
vitamin D status, GAD65 antibody titer, genetic status and immunological testing 
should be collected in accordance with Table 2 and Table 3.  
The total volume of blood that will be collected from each patient for diabetes status, 
laboratory safety assessments, vitamin D status, GAD65 antibody titer assessments 
and immunological testing will be approximately 438 mL for Main Study Period and 
additional approximately 80 mL for Extension Study Period. 
 
9.6 
Covid-19 serological testing 
 
Covid-19 is a condition that greatly affects the immune system and therefore its 
influence on the safety and efficacy of the GAD65 treatment as well as a potential 
direct effect on diabetes disease status in affected patients will be assessed. 
Serological testing for Covid-19 will allow the analysis of the infection’s effect on 
GAD65 treatment efficacy and additionally inform actions to be taken in future trials. 

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Blood samples will be used to analyze the presence of antibodies (IgG and/or 
Immunoglobulin M [IgM]) against SARS-CoV2 viral proteins using validated 
antibody detection tests.  
Samples from patients completing their Visits 7 (after the 1st January 2020) and Visit 
8 will be analyzed.  
 
9.7 
Assessment of Quality of Life 
QoL will be assessed by including Questionnaire EQ-5D-5L at visits between baseline 
and Month 24 as described in Section 7.1 and Table 2 and Table 3. 
9.8 
Assessment of Pubertal Stage and Concomitant Medication 
Variables which will be evaluated include: 
• Pubertal Stage: 
For boys: tanner genital development (G1-G5), pubertal hair (PH1-
PH5) and testicular volume (ml). 
For girls: Tanner breast (B1-B5) and pubertal hair (PH1-PH5) 
• Concomitant medication 
The timing of the assessments is described in Section 7.1 and Table 2 and Table 3. 
9.9 
Demographics and Other Baseline Characteristics 
9.9.1 
Demographics and Baseline Data 
The following demographic and baseline data will be collected at the Screening visit 
(Visit 1): 
• Age 
• Sex    
9.9.2 
Medical History 
Medical history will be recorded at the Screening visit (Visit 1).  
A complete review of the patient’s past medical history will be undertaken by and 
documented on the Medical History eCRF at the screening visit (Visit 1).  
All pre-existing conditions/diseases will be reported on the Medical History eCRF 
page at the screening visit (Visit 1).  
Medical histories will be coded using the current version of MedDRA. 
 
9.9.3 
Family History of T1D 
The patient’s T1D diagnosis date and family history of T1D will also be documented. 
 
 

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10 TREATMENT OF PATIENTS 
10.1 
Study Treatment 
Study medication: Diamyd® intralymphatic injection 
Diamyd/placebo will be injected directly into the inguinal lymph node at Visits 3, 4 
and 5 (Days 30, 60 and 90). The Diamyd/placebo injection directly into the inguinal 
lymph node need to be done by an appropriately qualified person at the X-ray 
department by help of ultrasound technique. All possible efforts should be made to 
use the same lymph node for all 3 injections. For more information regarding the 
injection please refer to the operations manual for the injection procedure. Upon 
trouble finding a suitable inguinal lymph node for injection on one side, the other side 
should be inspected. Only under exceptional circumstances can the injection be given 
into an axillary lymph node.  
 
After the injection, the patient shall remain in the vicinity of the study site for the next 
hour, and the injection site will be examined by investigator/study nurse 1 hour post 
injection. 
 
Study Medication: Vitamin D 
Treatment with vitamin D/placebo starts at Visit 2 if the Vitamin D serum levels are 
below 100 nmol/L (40ng/ml) at screening. If the patient has Vitamin D serum levels 
above 100 nmol/L (40 ng/ml) at screening, no Vitamin D/placebo treatment will be 
given to that patient (the patient will only be given the Diamyd/placebo injection). 
Patients with vitamin D levels below 100 nmol/L (40 ng/ml) at screening will receive 
vitamin D/placebo administered orally (2000IE per day) for 4 months (120 days in 
total). The patient should be instructed to return all used and unused vitamin 
D/placebo bottles at Visit 6. 
10.1.1 
Method of Assigning Patients to Treatment Groups 
A computer-generated randomization list will be produced by the IWRS system. After 
confirmation of eligibility at Visit 2 patients will be randomized in a 1:1 ratio 
(Arm 1:Arm 2) across all study sites. Randomization will be stratified by country and 
GAD65A level to ensure that an equal number of patients in respective age group are 
included in each arm.   
• Arm 1: Diamyd + vitamin D  
• Arm 2: Placebo for Diamyd + Placebo for vitamin D 
10.1.2 
Blinding and Code Breaking 
Patients, investigator site staff, persons performing the assessments, and data analysis 
will remain blind to the identity of the treatment from the time of randomization until 
database lock, using the following methods:  
 
(1) Randomization data are kept strictly confidential until the time of unblinding, and 
will not be accessible by anyone else involved in the study, except for the 
independent, unblinded statistician who will have access to the randomization scheme 
and for the purpose of providing unblinded safety data to the DSMB. 
 

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(2) The identity of the treatments will be concealed by the use of matching placebo to 
the study drug that are identical in packaging, labeling, appearance and schedule of 
administration. 
 
All respective study drugs will have the same treatment number printed on respective 
label. All three vials of Diamyd/placebo will be packed into one box per treatment 
number. The vial box and vials will all be labeled with the same treatment number. 
Allocation of treatment to Diamyd/placebo and vitamin D/placebo will follow a pre-
produced randomization list.   
 
Assignment of treatment number will be performed via a IWRS at Visit 2 for each 
individual patient. The randomization in IWRS will allocate the patient to one of the 
treatment arms in random order. 
 
Study medication will be shipped from the central depot to the study sites according 
to country specific laws and regulations, and the procedures will be described in the 
Study Drug Accountability Document. Eligible patients will be given study 
medication on Visit 2 (Day 1), 3, 4 and 5 according to the treatment number provided 
by the IWRS.   
 
The treatment code may be broken on an individual basis, in case of an SAE for 
which the investigator must know the study agent identity to initiate appropriate 
treatment. The investigator will be supplied with necessary information to break the 
study blind on an individual patient basis. If the study blind is broken, the investigator 
must inform the medical monitor or designee and report the reason for unblinding. 
The date, time, and reason for unblinding, together with the investigator’s signature, 
must be recorded. Patients will continue in the study unless this is deemed 
inappropriate. 
 
SUSARs will be unblinded for reporting to regulatory agencies and IECs. 
 
 pharmacovigilance center will be supplied with necessary information 
to break the study blind for individual patients as required for regulatory reporting 
purposes.  However, the investigator, Sponsor, and study team will be kept blinded to 
treatment allocation.  The information with regards to unblinding will be stored in a 
secure environment within the pharmacovigilance department and accessible only to 
pharmacovigilance staff. 
 
The code will be broken when all patients have completed the Main Study Period of 
15 months, and all data for this period has been entered into the database and the 
database has been locked. After database lock, the results will be analyzed and 
unblinded to the Contract Research Organization (CRO) statistician, CRO 
programmer, CRO personnel involved in the preparation of the clinical study report, 
Coordinating Investigator, and Sponsor.  The study will be kept blinded to patients, 
investigators, study nurses and study personnel (i.e. monitors, study coordinators etc.) 
during the 9-month Extension Study Period, i.e. the whole study period of 24 months. 
After the whole study period is completed a 24-month analysis will be performed. 
 
 

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10.1.3 
Study Medication 
The following medication supplies will be used in the study: 
 
A. 
Study medication:  
 
Diamyd® intralymphatic injection 
 
Dosage and interval: 4 µg (0.1 ml) will be administered 
directly into the inguinal lymph node (by an 
appropriately qualified person by help of ultrasound 
technique) at 3 occasions with one month intervals (at 
Days 30, 60 and 90). 
 
Comparator:  
 
Placebo intralymphatic injection 
 
IMP supplier:  
 
Diamyd Medical AB, 
. 
 
B. 
Study Medication: 
 
Vitamin D, 25 drops 
 
2 000 IU per day, given per os from Day 1 through 
Day 120 Trade name: 
 
 
 
Comparator:  
 
Placebo oral drops, solution 
 
IMP supplier: 
 
 
 
The doses are chosen according to Section 4 (Introduction and rational for the study) 
10.1.4 
Supply, Packaging, Handling and Storage 
 
  
 
Diamyd/Placebo will be supplied as pre-packed medication to a central depot who 
will distribute to the clinical site or local pharmacy. All dosing will take place in the 
hospital, and handled only by trained and authorized study personnel. 
 
Diamyd/Placebo must be stored in a refrigerator at 2-8 ºC in a secure area (e.g. a 
locked cabinet or drug storage room), protected from unintended use. 
 
Vitamin D/Placebo should be stored at room temperature (< 25 ºC) in a secure area 
(e.g. a locked cabinet or drug storage room), protected from unintended use. 
 
Vitamin D/Placebo will be distributed by a central depot, who will then distribute to 
the clinical site or local pharmacy.  
 

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All study medication will be labelled with information according to national and local 
regulations. 
10.2 
Treatment Compliance 
The Diamyd/Placebo administered directly into the inguinal lymph node (by an 
appropriately qualified person) need to be done at the X-ray department by help of 
ultrasound technique. For more information regarding the injection please refer to the 
operations manual for the injection procedure.  
10.3 
Study Medication Accountability 
All study medications supplied for this study must be retained in a safe place at all 
times of the study. Only personnel authorized by the investigator should dispense the 
study medication, and the accountability is the responsibility of investigator.  
 
The patient should be instructed to return all used and unused vitamin D/placebo 
bottles at Visit 6. 
 
A study medication inventory (dispensing records) for all medication dispensed must 
be maintained at all times and always kept current. Used and unused medication must 
be stored at the site or pharmacy throughout the study. The investigator/pharmacist 
must keep record of all drugs received, used and returned. Both pharmacies and study 
sites are obliged to properly measure and record the storage temperature. 
 
When the study is completed all unused and used study medication containers must be 
returned to the drug supplier unless the drug supplier has approved other 
arrangements.   
10.4 
Concomitant Therapy 
The patients will receive adequate therapy for concomitant diseases at the discretion 
of the investigator. Patients receiving a drug listed under exclusion criteria at 
screening should not be included in the study. Patients who are prescribed a drug 
listed in the exclusion criteria during the period between screening and first injection 
should be withdrawn from the study.   
 
Any concomitant medication must be recorded in the eCRF. Note: if a new 
medication is introduced or an existing medication is changed due to a new medical 
condition or worsening of a pre-existing medical condition, the condition must be 
reported as an AE.   
10.5 
Post Study Treatment 
No study medication will be offered to the patients after completion of the last injection. 
Patients will thereafter receive therapy at the discretion of the investigator and 
according to prescriptions. 
 
 

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11 ADVERSE EVENTS 
11.1 
Definitions of Adverse Events (AE) 
An AE is defined as any untoward medical occurrence in a subject during a clinical 
study administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment(s).  
 
An AE can therefore be any unfavorable and unintended clinical sign or symptom, 
any illness or disease, which develops or worsens in intensity during the course of the 
trial. It also includes an abnormal laboratory finding, if e.g., the abnormality results in 
trial withdrawal, is serious, is associated with clinical signs or symptoms, or is 
considered being of clinical relevance. 
 
It could also include accidents and reasons for changes in medication (drug and/or 
dose), any medical/nursing/pharmacy consultation and admission to hospital/surgical 
operations. 
 
Any new findings, clinically significant laboratory values or worsening of pre-existing 
condition must be reported as an AE by the investigator, whether or not considered 
related to the medicinal product(s). 
 
Note that hospital admission and/or surgical operations for illness, which existed 
before the study drug was given or the subject was enrolled in the clinical trial and did 
not worsen during the study, are not AEs. 
 
T1D-related events 
The number of self-reported episodes of severe hypoglycemia (Severe hypoglycemia 
defined as needing help from others and/or seizures and/or unconscious) between 
baseline and subsequent visits will be collected in the eCRF. Hypoglycemia, changes 
in C-peptide, changes to insulin dosage, and increases in HbA1c/blood glucose will 
not be reported as AEs unless the definition of SAEs is met.   
11.2 
Seriousness 
A SAE is defined as: an AE that is fatal, life-threatening, significantly or persistently 
disabling, requiring hospitalization or prolongation of existing hospitalization or that 
is a congenital anomaly or birth defect. 
 
These characteristics/consequences have to be considered at the time of the event. For 
example, regarding a life-threatening event, this refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.  
 
Some medical events may jeopardize the subject or may require an intervention to 
prevent one of the above characteristics/consequences. Such events (referred to as 
important medical events) should also be considered as serious in accordance with the 
definition.  
11.3 
Intensity 
Mild:   
The AE is transient and easily tolerated. 

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Moderate:  
The AE causes the patient discomfort and interrupts the patient's usual 
activities. 
Severe: 
The AE causes considerable interference with the patient's usual 
activities, and may be incapacitating or life-threatening. 
 
Note: a distinction should be drawn between serious and severe AEs. The term severe 
is used to describe the intensity of the event and the event does not necessarily need to 
be considered serious. The term serious is based on the patient/event outcome or 
action and serves as a guide for defining regulatory reporting obligations. 
11.4 
Relationship to Study Medication 
Relationship to study medication will be assessed for the two treatments (Diamyd and 
Vitamin D) separately. AEs with a causal relationship assessment of Unlikely related, 
Possibly related and Probably related will be considered to be Adverse Reactions. 
 
Not related: This category is applicable to those AEs which, after careful medical 
consideration at the time they are evaluated, are judged to be clearly and 
incontrovertibly due to extraneous causes (disease, environment, etc.) and do not meet 
the criteria for study medication relationship listed under remote, plausible or 
probable. 
 
Unlikely related:  Time relationship non-existent or doubtful and/or other factor(s) 
certain or probable to have been causative. 
 
Possibly related:  Time relationship exists.  Other possible causative factor(s) may 
exist (e.g., concurrent disease or concomitant medication).  Improvement on 
dechallenges or dose reduction may or may not have been seen.   
 
Probably related:  Time relationship exists.  No other possible causative factor(s) may 
exist (not reasonably explained by the patient’s known clinical state or concomitant 
medication).  Improvement on dechallenges or dose reduction (if performed) has 
occurred.  Recurrence of symptoms on rechallenge (if performed) has occurred.  A 
specific laboratory investigation (if performed) has confirmed the relationship. 
 
11.5 
Reporting of Adverse Events  
All AEs must be recorded in the eCRF, defining relationship to study medication, 
intensity, seriousness, action taken with study drug, and outcome. AEs should also be 
recorded by the investigator in the patient file/notes.  
11.6 
Timelines and Reporting of SAE 
All SAEs must be reported, whether or not considered attributable to the study drug 
on a separate SAE Report Form. SAEs will be reported from signing of informed 
consent. 
 
 will be responsible for reporting all SAEs in accordance 
with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and local 
regulations. The sponsor and 
will complete and sign a “Pharmacovigilance 
Working Agreement” agreement covering the safety reporting responsibilities in the 

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study. This agreement will ensure the sponsor is directly informed of each SAE 
reported by the investigators. 
In order to meet the specified reporting requirements investigators should adhere to 
the following process for recording and reporting SAEs.  
 
It is the investigator’s responsibility to, as soon as he/she is aware of a potential SAE, 
he/she should contact 
 by fax or e-mail, and in any case no later than 24 hours 
after the knowledge of such a case.  
At the time of initial reporting, the investigator must provide as a minimum 
requirement, the patient number, birth date, nature of the SAE, and a preliminary 
assessment of causality. The investigator should follow-up the initial notification of 
the potential SAE by faxing or e-mailing a copy of the SAE reporting form to 
 at 
the numbers/e-mail address provided in the investigator Site File and on the SAE 
Report Form. The faxed/e-mailed SAE Reporting Form should be received by 
 
within 24 hours of the initial notification of the event.  
 
It is the investigator’s responsibility to report to 
 follow-up information on an 
existing SAE that is fatal or life-threatening within 5 days after the initial report. 
Where appropriate, hospitalization or autopsy reports should be made available. All 
SAEs will be followed up until resolution (i.e., asymptomatic, stabilization or death).  
 
It is 
 responsibility to receive e-mail or fax copies of the SAE report form and 
other relevant eCRF pages from the investigators. The Drug Safety unit at 
 will 
review the information provided on the form and enter it into the safety data base. The 
SAE report will be assigned a unique number that will be entered on the SAE Report 
Form, and will be used to identify the report in all future communication. A 
notification of receipt of the report will be sent to the reporter, either by fax or e-mail 
within 48 hours. 
 will contact the investigator directly if there is any 
inconsistencies and missing information. 
 
 is responsible for the timely submission of SUSARs to the Competent 
Authorities and IECs according to appropriate Competent Authority and IEC 
requirements. It is 
s responsibility to report SUSARs to investigators according 
to ICH GCP and to local regulations. Competent Authorities will be notified of all 
SUSARs through the EudraVigilance database.  
 
Fatal and life-threatening SUSARs should be reported by 
 as soon as possible to 
the Competent Authorities and Ethical Committees, and in any case no later than 
seven (7) calendar days, after knowledge by the Sponsor/
 of such a case. Relevant 
follow-up information on the case will be subsequently communicated within an 
additional eight (8) days. All other SUSARs shall be reported to the Competent 
Authorities concerned and to the Ethics Committee concerned as soon as possible but 
within a maximum of fifteen (15) days of first knowledge by 
  
11.7 
Unresolved Events 
If an AE/SAE is present when the patient has completed the study the course of the 
event must be followed until final outcome is known or the condition is stable. 

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11.8 
Pregnancy Report Form 
Pregnant and lactating women will not be included in the study. Menarchal females 
must have a negative urine pregnancy test prior to randomization and a negative urine 
pregnancy test at each study visit with Diamyd/Placebo administration, prior to 
injection of study drug. Patients will be required to use an adequate form of birth 
control during the study. At Visit 2 the need for birth control will be re-assessed. 
Patients and their partners will be strongly advised to avoid pregnancy for 1 year 
following the last dose of Diamyd/Placebo and instructed to use adequate birth 
control. 
 
A pregnancy occurring during the trial must be recorded on the Pregnancy Report 
Form and no further drug doses will be given. If the pregnancy is verified prior to any 
of the injections, no further injection shall be given. 
 
The Pregnancy Report Form should be faxed or e-mailed within 24 hours of 
awareness to 
. A copy of the report should be filed at the study site for follow-up 
until delivery. Any pregnancy must be followed until delivery or to the end of 
pregnancy. 
11.9 
Direct Access to Source Data/Documents  
The sponsor should ensure that it is specified in the protocol or other written agreement 
that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IEC 
review, and regulatory inspection(s), providing direct access to source data/documents. 
 
 

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12 DATA HANDLING 
12.1 
Data Management 
Data management and handling of data will be conducted according to the study 
specific Data Management Plan with ICH guidelines and 
 standard operating 
procedures (SOPs). 
 
An eCRF system will be used to capture data from the study. Data entry will be 
performed by the study site personnel. Validation and data queries will be handled by 
the 
 Data Management Team. The data will be subjected to validation according 
to 
 SOPs in order to ensure accuracy in the collected eCRF data. 
 
Changes to the data in the eCRF will be made at the site by the study site personnel. 
The eCRF will have an audit trail with appropriate functionality for data capture, 
tracking and documentation of any queries or changes. Electronic signatures will be 
used to lock the data and identify the person entering or changing the data. 
Before database closure a reconciliation will be performed between the SAEs entered 
in the safety database and the study database. After database closure, the database will 
be exported as SAS® data sets. 
 
Any deviations, i.e. discrepancies and additions from the process defined in the Data 
Management Plan, will be described in a study specific Data Management Report. 
 
 
 

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13 STATISTICAL METHODS 
13.1 
Estimation of Sample Size 
A total sample size of 106 patients is planned for a 1:1 randomization in order to 
provide 90% power to detect a 50% difference in geometric mean C-peptide 
(AUCmean 0-120 min) during an MMTT at 15 months between the active arm and placebo 
arm using a two-sided test at the 0.05 significance level. The sample size has been 
adjusted to allow for 10% loss to follow-up. This is based upon a t-test employing 
ln(X+1) normalizing transformation of C-peptide (AUCmean 0-120 min) during an MMTT 
at 15 months and assumed mean and standard deviation estimates, on the transformed 
scale, of 0.134 and 0.20, respectively1 
It is estimated that there will be a screening failure rate of 16%. To ensure that 
106 patients are screened and enrolled approximately 127 patients will be screened. 
13.2 
Statistical Analyses 
A detailed statistical analysis plan (SAP) will be written and finalized well in advance 
of database lock. The plan will follow the outline of the statistical analyses presented 
below, but details necessary to complete the statistical analyses will be given. 
 
13.2.1 
Data Sets to be Analyzed 
The following analysis sets will be used for the statistical analysis and presentation of 
data:  
• The screened set will consist of all patients that were screened for 
participation in this study 
 
• The randomized set will consist of all patients that were randomized. 
 
• The Safety Set will consist of all randomized patients who received at least 
one injection. 
 
• The Full Analysis Set (FAS) will consist of all randomized patients who have 
received at least one dose of study medication and have at least one post-
baseline assessment and corresponding baseline measurement of any efficacy 
variable. 
 
• The Extension set will consist of the subset of the FAS that participated in the 
Extension Study Period.  
 
• The Completers Set will consist of all patients in the FAS who have 
completed the main study period and who have primary efficacy data available 
at Visit 7. 
 
• The Per Protocol Set (PPS) will consist of all patients in the FAS who 
received all three study drug injections, and do not have any other major 
 
1 Lachin et.al Sample Size Requirements for Studies of Treatment Effects on Beta-Cell 
Function in Newly Diagnosed Type 1 Diabetes, 2011, 6(11):e26471 

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protocol violations which will affect the assessment of efficacy. Major 
protocol violations include:  
 
o Missed at least one scheduled injection of IMP 
o C-peptide samples received by lab later than 48 hours after sampling 
 
 
The final criteria for PPS, regarding which protocol deviations that warrant 
exclusions, will be determined when all data on protocol violations/deviations are 
available and before breaking the blind. The final criteria will be documented in the 
SAP or in the Pre-Analysis Review form issued by the statistician prior to unblinding 
of the data. 
 
The Screened set will be used for presentation of study disposition of patients. 
 
The FAS is considered as the primary analysis dataset, and will be used for all 
primary, secondary and exploratory efficacy endpoints. The primary efficacy analyses 
will be repeated using the PPS and the completers set and these analyses will be 
regarded as sensitivity analyses. Any discrepancy between the results from the FAS 
and the PPS or the completers set will be analyzed and discussed in the Clinical Study 
Report. 
The secondary variables will be analyzed based on FAS only. 
The analysis datasets will be applied at the main study analyses as well as the whole 
study period.  
 
Baseline presentations will be based on the safety set and on the FAS. Safety 
presentations will be based on the safety set. FAS will be analysed according to 
randomised (planned) treatment. Safety and PPS will be analysed on actual treatment 
received. 
 
13.2.2 
Statistical and Analytical Plan 
In general, data will be presented using summary statistics. For continuous variables 
number of observations, mean, standard deviation, minimum, median, and maximum 
will be given. Categorical variables will be presented as frequencies and percentages.  
For all statistical analyses, p-values and 95% confidence intervals will be given. The 
tabulation of the descriptive statistics will be split by treatment group and visit, as 
applicable.  
 
13.2.2.1 Demographic and Other Baseline Characteristics 
Demographics and baseline characteristics will be presented using summary statistics 
for each treatment group and in total. 
13.2.3 
Hypotheses and Statistical Methods 
13.2.3.1 Analysis of Primary Endpoint Variable 
The primary efficacy variable will be change in log-transformed C-peptide 
AUCmean 0-120 min during an MMTT from baseline to Month 15. Mean changes from 
baseline will be analyzed using Mixed Model Repeated Measures (MMRM). The 
model for analysis will include fixed, categorical effects of treatment, randomization 

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strata (GAD65A level), visit and treatment by visit interaction, as well as the 
continuous, fixed covariates of log-transformed baseline C-peptide AUCmean 0-120  
during an MMTT. An unstructured (co)variance structure will be used to model the 
within-patient errors. If this analysis fails to converge, compound symmetry will be 
tested. The (co)variance structure converging to the best fit, as determined by 
Akaike’s information criterion will be used as the primary analysis. The Kenward-
Roger approximation will be used to estimate denominator degrees of freedom. The 
primary treatment comparison will be the contrast between treatments at Month 15 for 
active treatments versus placebo. 
Least Square (LS) Mean estimates and 95% confidence intervals (CIs) will be back-
transformed from the log scale to the original scale and given together with nominal 
p-values. Back-transformed estimates of the treatment difference will provide an 
estimate of the (Diamyd/placebo)-ratio in the relative change from baseline in AUC. 
Here a ratio of e.g. 0.8 will mean that the change from baseline to month 15 in C-
peptide level was 20% smaller for Diamyd than for placebo at Month 15.  
A sensitivity analysis where the hypotheses will also be assessed using Analysis of 
Covariance (ANCOVA) adjusted for baseline value of C-peptide (AUCmean 0-120 min) 
during an MMTT between baseline to 15 months and randomization strata (GAD65A 
level) using the completers set.  
Further sensitivity analyses will be given in the SAP.  
13.2.3.2 Analysis of Secondary Endpoint Variables 
 
13.2.3.2.1 Key Secondary Variables of Diabetes Status 
The following key secondary efficacy endpoint variables will be analysed with the 
same model (MMRM) as the primary efficacy endpoint: 
 
• Change in IDAA1c between baseline and 15 months. 
• Change in HbA1c between baseline and 15 months. 
• Change in daily exogenous insulin consumption between baseline and 15 
months. 
 
The analysis of key secondary endpoints will be subject to the same sensitivity 
analyses as the primary efficacy analysis. However, exploration of key secondary 
endpoints by covariate and subgroups analyses will be based on the observed results 
for respective endpoint.  
 
13.2.3.2.2 Other Secondary Variables of Diabetes Status 
Summary statistics (including Student’s t based 95% CIs and p-value for the 
difference between Diamyd and Placebo) for change in glycemic 
variability/fluctuations (evaluated from data from continuous glucose monitoring 
FreeStyle LibrePro, FGM) over 14-day period between Screening and 15 months. 
Further analysis of the data from the 14-day FreeStyle LibrePro, periods will be 
presented in the SAP. 
 

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The following secondary efficacy endpoint variables will be analyzed with the same 
model as the primary efficacy endpoint (details on log-transformations will be given 
in the SAP): 
• Proportion of patients with by IDAA1c ≤9 at 15 months. 
• Change in Fasting C-peptide between baseline and 15 months. 
• Change in C-peptide measured at 30, 60, 90, and 120 minutes during MMTT 
at 15 months. 
• Change in maximum C-peptide during MMTT between baseline and 
15 months. 
 
The following secondary efficacy endpoints will be presented using summary 
statistics and p-value from Cochran/Mantel-Haenszel Test stratified for randomization 
strata (GAD65A level) will be given along with 95% CIs calculated according to the 
Clopper-Pearson method: 
• Proportion of patients with a stimulated maximum C-peptide level above 
0.2 nmol/L (0.6 ng/ml) at 15 months. 
• Proportion of patients with a stimulated 90min C-peptide level above 
0.2 nmol/L (0.6 ng/ml) at 15 months. 
• Number of patients having at least 1 severe hypoglycemic event using 
Cochran/Mantel-Haenszel Test stratified for randomization strata (GAD65A 
level). 
• Change in body weight and BMI between baseline and 15 months 
 
In addition, the number of self-reported episodes of severe Hypoglycaemia (severe 
Hypoglycaemia defined as needing help from others and/or seizures and/or 
unconscious) between baseline and 15 months will be assessed using Poisson 
regression including randomization strata (GAD65A level) where rate ratios with 95% 
CI and p-value will be given.  
 
 
 
13.2.3.3 Analysis of Exploratory Endpoint Variables 
 
All data collected at the 24-month follow-up visit (Visit 8) will be regarded as 
exploratory endpoints and will be presented using summary statistics including data 
from the Main Study Period where only the patients that participated in the Extension 
Study Period will be included. The following statistical analyses will be repeated for 
the whole study period:  
 
• The change in log-transformed C-peptide AUCmean 0-120 min during an MMTT 
from baseline to Month 24 
• Change in HbA1c between baseline and 24 months 
• Change in daily exogenous insulin consumption between baseline and 
24 months 
• Change in Fasting C-peptide between baseline and 24 months. 

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• Change in glycemic variability/fluctuations (evaluated from data from 
continuous glucose monitoring FreeStyle LibrePro, FGM) over 14 day period 
between Screening and 24 months. 
• Rate of hypoglycemic events using Poisson regression including 
randomization strata (GAD65A level) 
• Number of patients having at least 1 severe hypoglycemic event using 
Cochran/Mantel-Haenszel Test stratified for randomization strata (GAD65A 
level) 
• Change in body weight and BMI between baseline and 24 months 
 
 

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13.2.3.3.1 Secondary Safety Variables 
 
Adverse events:  
AEs will be coded according to the MedDRA system and tabulated by System Organ 
Class (SOC) and by preferred term. 
A summary table will be presented with total number and No. of patients with: 
• AEs 
• serious AEs 
• related AEs 
• AE leading to discontinuation 
AE will only be counted once within each patient on a preferred term level. 
The total number of patients with at least one AE and the number of AEs will be 
derived and summarized by SOC and preferred term. 
AEs will also be tabulated versus intensity and relationship to treatment (classified as 
related for outcomes “Remote”, “Plausible” and “Probable” and not related for 
outcome “Unrelated”. If a patient has more than one event classified with the same 
preferred term, then the worst intensity and the worst relationship will be used. In this 
table, patients having AEs will be identified by their patient number.  
A treatment-emergent AE (TEAE) is an event emerging after treatment start or 
worsening during treatment. Hence, events with an onset time on or after the time of 
treatment start are treatment-emergent. Only TEAEs will be included in summary 
tables. Pre-treatment AEs will be listed.  
Treatment-emergent serious adverse events (TESAEs) will be listed separately.   
In listings of AEs the relative day of occurrence will be given. Relative day will be 
calculated as (Date of first administration of IMP – AE start date) + 1 for AEs 
occurring on date of first administration of IMP or later and as (Date of first 
administration of IMP – AE start date), otherwise. 
AEs will be presented for the main study period and for the whole study period.   
Other safety endpoints: 
All other safety endpoints will be presented using summary statistics. These 
presentations will be done for the Main Study Period and the whole study period 
where only the patients that participated in the Extension Study Period will be 
included. For laboratory measurements and vital signs change from baseline will also 
be summarized. Shift tables will present shifts for all endpoints for which 
normal/abnormal (Not Clinically Significant/Clinically Significant [NCS/CS]) 
judgements exist. 
 

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13.2.3.3.2 Secondary Immunological Variables 
Immunological secondary endpoints will be presented in summary statistics and will 
be accompanied with p-values from non-parametric statistical tests (details to be given 
in SAP). 
 
 
13.2.3.3.3 Secondary Variables of Quality of Life 
Analysis of the QoL data obtained within the study will follow the EQ-5D-5L User 
guide. 
13.2.4 
Level of Significance, Multiple Comparisons and Multiplicity 
The primary endpoint and the key secondary endpoints will be tested hierarchically at 
the 5% significance level. This implies the following testing sequence:  
 
1. Change in C-peptide AUCmean 0-120 min during a MMTT between baseline and 
15 months. 
2. Change in IDAA1c between baseline and 15 months. 
3. Change in HbA1c between baseline and 15 months. 
4. Change in daily exogenous insulin consumption between baseline and 15 
months. 
 
13.2.5 
Adjustment for Covariates 
Change from baseline analyses will be adjusted for baseline and all other analyses will 
be adjusted for randomization strata (GAD65A level).   
13.2.6 
Handling of Dropouts and Missing Data 
This MMRM suggested for the primary efficacy analysis does not require imputation 
of missing data. Instead missing data is modeled based on the patient’s available data 
and on other patients’ developments over time.  
13.2.7 
Multicenter Studies 
As the number of centers are large in relation to the number of patients to be included, 
no by-center displays are planned. 
13.2.8 
Examination of Subgroups 
Efficacy variables will be explored within the subgroup of patients with HLA 
haplotype DR3-DQ2 (versus not DR3-DQ2). The details of the analyses will be 
specified in the SAP. 
13.2.9 
Interim Analysis and Data Monitoring 
No formal interim analysis will be performed.  
An independent DSMB will be appointed. The DSMB will review the safety data 
throughout the study period twice a year. For further details, please see the DSMB 
charter and the DSMB SAP. 
13.2.10 
Deviation(s) from the Statistical Analysis Plan 
Any deviation from the final SAP should be stated in the final clinical report. 
 
 

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14 REGULATORY AND ADMINISTRATIVE PROCEDURES  
 
14.1 
Ethics Committees and Competent Authorities 
Any regulatory requirements must have been met before starting the study. The 
Sponsor will apply for the regulatory approval to the appropriate authorities. 
 
Study sites, facilities, laboratories and all data (including source data) and 
documentation must be made available for inspection by the authorities. 
 
The study will be conducted in accordance with the Brazil (2013) amendment to the 
Declaration of Helsinki 1964. 
 
The Protocol and Patient Information and ICF will be approved by the Ethics 
Committee before commencement. If a substantial protocol amendment is necessary, 
this will be signed and submitted by the Sponsor for ethical and regulatory approval. 
The approval from the Ethics Committee and Competent Authority should be 
obtained before any implementation of the amendment is done. When the change or 
deviation is to eliminate or reduce risk to human patients, the amendment may be 
implemented before review of approval by the Ethics Committee and Competent 
Authority. The sponsor should notify the Ethics Committee and Competent Authority 
of the change or deviation in writing within 10 working days after implementation. 
 
Minor amendments which do not affect the safety or conduct of the study from the 
patient viewpoint, and which do not significantly reduce the scientific value of the 
protocol, and which do not require a significant change to be made to the consent 
form and/or the information sheet, will not be submitted for formal ethics and 
regulatory review. These will be sent to the Ethics committee and Competent 
Authority on an ‘information only’ basis. 

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14.2 
Patient Information / Informed Consent  
The investigator is responsible for giving the patients and his/her parents/caregivers (if 
applicable) full and adequate verbal and written information about the nature, purpose, 
possible risk and benefit of the study. Patients and, if applicable, his/her 
parents/caregivers must also be notified that they are free to withdraw from the study 
at any time. The patients and parents/caregivers should have reasonable time to read 
and understand the information before signing. The investigator is responsible for 
obtaining signed informed consent from all patients before including the patient in any 
study related procedures. 
 
Should there be any amendments to the final protocol, such that would directly affect 
the patient’s participation in the trial e.g., a change in any procedure, or if new data is 
obtained during the trial that may influence the standpoint to participate in the study, 
the patient information will be amended to incorporate this modification and the 
patient must agree to sign this amended form verifying that they re-consent to 
continue their participation in the trial. 
 
A copy of the Patient Information and of the ICF will be given to the patients and 
parents/caregivers. 
14.3 
Patient Confidentiality 
The investigator must ensure that patient's confidentiality will be maintained. eCRFs 
or other documents submitted to the Sponsor should only identify patients by their 
initials and study number. The investigator should keep a separate log of patient codes 
and names. 
 
Documents not for submission to the Sponsor, e.g. patient's completed Consent 
Forms, should be retained by the investigator in strict confidence.  
 
The investigator is required to record safety data, concomitant medication and patient 
progress in the patient's file/notes/medical record. 
 
The patient's medical records will be reviewed by the study monitor to verify adequate 
source documentation, accuracy and completeness of eCRFs. The review will be 
conducted with strict adherence to professional standards of confidentiality. 
 
The investigator must keep a screening log, recording all patients who were screened, 
whether they were enrolled or not, and a separate Patient Identification List showing 
code numbers, names, and dates of birth to allow unambiguous identification of each 
patient included in the study. 
14.4 
Patient Treatment Plan 
All patients will continue to receive standard care for T1D during the study. 
 
After the individual completion of the study, the patient will return to the standard 
treatment received prior to study participation. 

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14.5 
GCP 
The study will be managed and conducted in compliance with the protocol and 
according to the latest international (ICH) guidelines for GCP as well as the 
applicable regulatory requirement(s). 
14.6 
Record Retention 
The eCRFs and all medical records upon which the eCRFs are based (source data) 
must be kept for at least 10 years, or the length of time according to local legislations, 
whichever is longer, after completion of the study.  
The Investigator/institution should maintain essential documents (as defined in ICH 
E6 GCP, Section 8) as required by the applicable regulatory requirement(s). The 
Investigator/institution should take measures to prevent accidental or premature 
destruction of the documents. 
Essential documents should be retained according to applicable regulatory 
requirements of the country(ies) where the product is approved, and/or where the 
Sponsor intends to apply for approval. 
It is the responsibility of the Sponsor to inform the Investigator/institution in writing 
as to when the documents no longer need to be retained. 
14.7 
Monitoring / Quality Control 
Prior to the start of the study, the monitor will review the protocol and eCRFs with the 
investigator and his/her staff. The investigator will be visited by the monitor, who will 
check study procedures, including safety assessments, study medication handling, 
data recording and source data verification (SDV). To assure the accuracy and 
completeness of the data recorded in the trial, the monitor will compare eCRFs with 
medical records and other relevant documentation during the on-site monitoring visits. 
The monitor must therefore direct access to all source data according to ICH GCP to 
confirm that required protocol procedures are being followed and check consistency 
between patient record and eCRF data. Incorrect or missing entries into the eCRFs 
will be queried and must be corrected. Study monitoring will not jeopardize patient 
confidentiality.  
14.8 
Source Data  
Source data is defined as any information in original records and certified copies of 
original records of clinical findings, observations or other activities necessary for 
reconstruction and evaluation for the study (e.g. eCRFs, medical records (including 
EMRs) lab reports, patient information sheets, patient diaries, etc.).  
The origin of source data in the study will be further specified for each study site in a 
separate document (“Origin of Source Data”).  
It is the responsibility of the Investigator to record essential information in the 
medical records in accordance with national regulations and requirements. The 
following information should be included as a minimum: 
• A statement that the patient is in a clinical study 
• The identity of the study e.g. Study code 
• Patient screening number and/or patient number 
• That informed consent was obtained and the date 
• Diagnosis 
• Dates of all visits during the study period 

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• Any information relating to AEs 
• All treatments and medications prescribed/administered (including dosage) 
• Date of study termination 
• Patient health service identification number 
The Investigator is responsible for ensuring the accuracy, completeness, legibility and 
timeliness of the data recorded in the eCRFs. Data reported in the eCRF that are 
derived from source documents should be consistent with the source documents or the 
discrepancies should be explained. Signed sections of eCRFs will be monitored and 
collected on a regular basis. 
 
14.9 
Quality Assurance and Insurance 
During or after the study is completed, regulatory authorities, the Sponsor, 
 or 
other involved party may wish to carry out an audit. These representatives must have 
the same access to study data and patient source data as the monitor. 
 
The Sponsor is covered by a liability insurance that also covers liability towards 
patients in clinical trials 
 
 

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15  
END OF TRIAL 
The end of the trial is defined as the last visit of the last patient included in the trial 
and all data have been collected.  
15.1 
Study Report 
A clinical study report will be prepared covering clinical and statistical aspects and 
summarizing all findings of the Main Study Period. The data from the Extension Study Period 
will be summarized in an addendum to the final clinical study report from the Main Study 
Period. 
15.2 
Study Stopping Criteria 
The Sponsor and the investigators reserve the right to discontinue the study at any 
time for safety reasons or other reasons jeopardizing the justification of the study. 
Such a termination will be implemented in a time frame that is compatible with the 
patient’s wellbeing. 
 
If the study is prematurely terminated or suspended, the investigator should promptly 
inform the patients and assure appropriate therapy and follow-up. The Sponsor will 
notify the Regulatory Authorities and the IECs of any plans to terminate the study. 
15.3 
Publication  
It is intended that the results of the trial will be published in the scientific literature.  
Results may also be used for submissions to Regulatory Authorities. The following 
conditions are to protect commercial confidential materials (patents, etc.) and not to 
restrict publication. 
 
All information concerning trial drug (such as patent applications, formulae, 
manufacturing processes, or formulation information supplied to the investigator by 
the Sponsor and not previously published) is considered confidential by the Sponsor 
and shall remain the sole property of the Sponsor. The investigator agrees not to use 
this for other purposes without the Sponsor’s written consent. 
 
It is understood by the investigator that the Sponsor will use the information obtained 
in this clinical trial in connection with the development of the trial drug and therefore 
may be disclosed as required to other of the Sponsor’s investigators or any appropriate 
international Regulatory Authorities. In order to allow for the use of the information 
derived from this clinical trial, the investigator understands that he/she has an 
obligation to provide the Sponsor with complete test results and all data obtained 
during this trial. 
 
Prior to submitting the results of this trial for publication or presentation, the 
investigator will allow the Sponsor 30 days in which to review and comment upon the 
publication manuscript. The Sponsor agrees that before it publishes any results of this 
trial it shall provide the investigator at least 30 days for full review of the manuscript. 
Coordinating investigator will decide who should be authors/coauthors, and the order 
of authors. In accordance with generally recognized principles of scientific 
publication rules and collaboration, co-authorship with investigators and any of the 
Sponsor’s personnel will be discussed and mutually agreed upon before submission of 
a manuscript to a publisher. 
 

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Pediatric infectious disease journal. Jul 1 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 

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17 SIGNATURES  
This Clinical Study Protocol is approved by: 
 
Sponsors Representative:   
(Name, Title, Affiliation)  
 
 
(Signature) 
 
 
…………..………………………………………… 
 
Date:  ………………………….. 
 
Principal/Coordinating Investigator:   
(Name, Title, Affiliation)  
 
 
(Signature) 
 
 
…………..………………………………………… 
 
Date:  ………………………….. 
 
Other(s), as applicable:   
(Name, Title, Affiliation)  
 
 
(Signature) 
 
 
…………..………………………………………… 
 
Date:  ………………………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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18 CLINICAL STUDY PROTOCOL AGREEMENT FORM  
 
Investigator’s Statement: 
 
I have read and understand the foregoing protocol with the title:  
 
“A Phase IIb, 2-Arm, Randomized, Double-blind, Placebo-Controlled, Multicentre 
Study to Optimize Diamyd® Therapy Administered into Lymph Nodes Combined 
with Oral Vitamin D to Investigate the Impact on the Progression of Type 1 diabetes”. 
 
with study number DIAGNODE-2 (D/P2/17/6) and agree to conduct the trial, in 
compliance with ICH notes on Good Clinical Practice (CPMP/ICH/135/95), 
designated Standard Operating Procedures, National Laws and regulations and within 
the principles of the current revision of Declaration of Helsinki (Brazil 2013). 
 
Investigator’s Name:   
 
 
Investigator’s Title:   
 
 
Investigator’s Signature: 
 
 
…………..………………………………………… 
 
Date:  …………………………..