Diamyd Administered Into Lymph Nodes in Combination With Vitamin D in Type 1 Diabetes

Study Overview
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Brief Summary
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The objective of DIAGNODE-2 is to evaluate the efficacy of Diamyd compared to Placebo, upon administration directly into a lymph node in combination with an oral vitamin D/Placebo regimen, in terms of preserving endogenous insulin secretion as measured by C-peptide.

Detailed Description
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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 have not performed the 15 months visit when the updated protocol is implemented, will be asked to participate in the Extension Study Period which includes an additional visit at month 24.

Official Title
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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

Conditions
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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

Intervention / Treatment
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* Biological: Diamyd
* Dietary Supplement: Vitamin D
* Biological: Placebo for Diamyd
* Dietary Supplement: Placebo for Vitamin D


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent given by patients and/or patient's parent(s) or legal acceptable representative(s) (guardian(s)) according to national regulations Type 1 Diabetes (T1D) according to the Amercian Diabetes Association (ADA) classification diagnosed ≤6 months at the time of screening Age: ≥12 and <25 years old 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) Positive for Glutamic Acid Decarboxylase isoform 65 (GAD65A) but < 50 000 IU/ml 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: oral (except low-dose gestagen (lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives combined (estrogen and progestogen containing) oral, intravaginal or transdermal progesterone hormonal contraception associated with inhibition of ovulation intrauterine device intrauterine hormone-releasing system (for example, progestin-releasing coil) bilateral tubal occlusion vasectomized male (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate) male partner using condom abstinence from heterosexual intercourse For males of childbearing potential: condom (male) abstinence from heterosexual intercourse Exclusion Criteria: Previous or current treatment with immunosuppressant therapy (although topical or inhaled steroids are accepted) Continuous treatment with anti-inflammatory drug (sporadic treatment e.g. because of headache or in connection with fever a few days will be accepted) Treatment with any oral or injected anti-diabetic medications other than insulin A history of anemia or significantly abnormal hematology results at screening A history of epilepsy, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles Clinically significant history of acute reaction to vaccines or other drugs in the past 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. Participation in other clinical trials with a new chemical entity within the previous 3 months Inability or unwillingness to comply with the provisions of this protocol A history of alcohol or drug abuse A significant illness other than diabetes within 2 weeks prior to first dosing Known HIV or hepatitis 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) 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 Deemed by the investigator not being able to follow instructions and/or follow the study protocol

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is a 2-arm, randomized, double-blind, placebo-controlled, multicenter, clinical trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active arm<br>Patients will be assigned to receive i) three (3) intralymphatic injections with Recombinant human Glutamic Acid Decarboxylase adsorbed to Alhydrogel (Diamyd) on Days 30, 60, and 90 and; ii) oral vitamin D 2000 IU/daily for 4 months (from Day 1 through Day 120) | Biological: Diamyd<br>* Alhydrogel®-formulated recombinant human glutamic acid decarboxylase (rhGAD65)<br>* Other names: GAD-alum;Dietary Supplement: Vitamin D<br>* Oil suspension of Vitamin D<br>|
| Placebo Comparator: Placebo arm<br>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) | Biological: Placebo for Diamyd<br>* Alhydrogel® only<br>Dietary Supplement: Placebo for Vitamin D<br>* Placebo oil suspension for Vitamin D<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Stimulated C-peptide During a MMTT | Change in C-peptide between Baseline and 15 Months. C-peptide was measured by Area Under the Curve [AUC] at 0-120 min during a Mixed Meal Tolerance Test (MMTT) and divided by 120 min. The results are given as the ratio (back-transformed from log-scale) between 15 Months and Baseline as predicted by the MMRM (Mixed Model Repeated Measures) model. | Baseline and 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in IDAA1c | Change in insulin-dose-adjusted HbA1c (IDAA1c) | Baseline and 15 months | 
| Change in HbA1c | Change in HbA1c (mmol/mol) | Baseline and 15 months | 
| Change in Insulin Consumption | Change in daily exogenous insulin consumption (IU) | Baseline and 15 months | 
| Change in Glycemic Variability/Fluctuations | Change in glycemic variability/fluctuations (evaluated from data from continuous glucose monitoring FreeStyle LibrePro, FGM) over 14 day period. | Screening and 15 months | 
| Percentage of Patients With IDAA1c ≤ 9 | Percentage of patients with IDAA1c ≤ 9 | 15 months | 
| Stimulated Maximum C-peptide Above 0.2 Nmol/L | Percentage of patients with a stimulated maximum C-peptide level above 0.2 nmol/L (0.6 ng/ml) | 15 months | 
| Stimulated C-peptide Above 0.2 Nmol/L at 90 Min | Percentage of patients with a stimulated 90min C-peptide level above 0.2 nmol/L (0.6 ng/ml) | 15 months | 
| Number of Hypoglycemias | Number of self-reported episodes of severe hypoglycemia (Severe hypoglycemia defined as needing help from others and/or seizures and/or unconscious) (counts) | Baseline and 15 months | 
| Number of Patients Having at Least 1 Severe Hypoglycemic Event | Number of patients having at least 1 severe hypoglycemic event (counts) | Baseline and 15 months | 
| Change in Maximum C-peptide | Change in maximum C-peptide during MMTT (nmol/L) | Baseline and 15 months | 
| Change in Fasting C-peptide | Change in Fasting C-peptide (nmol/L) | Baseline and 15 months | 
| C-peptide Levels During a MMTT | C-peptide measured at 30, 60, 90, and 120 minutes during MMTT (nmol/L) at 15 months | 15 months | 
| Change in Body Weight | Change in body weight (kg) | Baseline and 15 months | 
| Injection Site Reactions | Injection site reactions | 15 months | 
| Number of Clinically Significant Abnormal Results From Laboratory Measurements (Haematology and Clinical Chemistry) and Urinalysis. | Number of clinically significant abnormal results from laboratory measurements (haematology and clinical chemistry) and urinalysis. (counts) | 15 months | 
| Number of Clinically Significant Abnormal Results From Physical and Neurological Examinations | Physical examination (general appearance including skin, mouth, throat, cardiovascular, abdomen, lymphatic glands, and neurological/musculoskeletal [including reflexes]). Standardised clinical neurological examination including extremity reflexes, Romberg, Walk on a line, 2 meters, Standing on 1 leg, left and right, 15 seconds per leg, Finger-nose, Mimic, Babinski reflex. The outcome of the assessments was recored as normal or abnormal | 15 months | 
| GAD65A Titer | GAD65A titer (IU/ml) | Baseline and 15 months | 
| Number of Clinically Significant Abnormal Results in Vital Signs | Vital signs (blood pressure) (mmHg) | 15 months | 
| Change in Quality of Life (QoL) | Change in QoL as measured by the standardised measure of health questionnaire EQ-5D-5L between baseline and Month 15. The EQ-5D-5L is based on 5 questions rated at 5 levels indicating from no problem (level 1) to extreme problems (level 5) regarding current state of mobility, self-care, activity, pain and anxiety. The outcome is presented as a weighted index value, where 1 is the best possible health and 0 represents being dead. | Baseline and 15 months | 
| Change in Body Mass Index (BMI) | Change in BMI (kg/m2) | Baseline and 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diamyd, Diabetes, Juvenile Diabetes, Diabetes Type 1, Type 1 Diabetes, Autoimmune Diabetes, Insulin Dependent Diabetes, Type 1 Diabetes Mellitus, rhGAD65, GAD65, Diabetes Mellitus, Diabetes Mellitus Type 1, Glucose Metabolism Disorders, Metabolic Diseases, Vitamin D, Vitamins, Micronutrients, Cholecalciferol, Ergocalciferols