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

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

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.

Study Overview

• Status: Completed
• Conditions: Glucose Metabolism Disorders; Immune System Diseases; Autoimmune Diseases; Diabetes Mellitus; Endocrine System Diseases; Diabetes Mellitus, Type 1; Metabolic Disease; Vitamin D; Autoimmune Diabetes; Physiological Effects of Drugs; Juvenile Diabetes; Insulin Dependent Diabetes
• Intervention / Treatment: Dietary supplement: Vitamin D; Dietary supplement: Placebo for Vitamin D; Biological: Diamyd; Biological: Placebo for Diamyd

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Praha, Czechia, 14021
    • Diabetes Centre, Institute of Clinical and Experimental Medicine
  • Praha, Czechia, 15006
    • Department of Paediatrics, University Hospital Motol
• Netherlands
  • Rotterdam, Netherlands, 3011 TA
    • Diabeter Rotterdam
• Spain
  • Barakaldo, Spain, 48903
    • Adult and Pediatrics Endocrinology and Diabetology, Hospital Universitario Cruces
  • Barcelona, Spain, 08035
    • Adult Endocrinology and Diabetology, Hospital vall D' Hebrón
  • Barcelona, Spain, 08035
    • Pediatrics Endocrinology and Diabetology, Hospital Vall D'Hebrón
  • Madrid, Spain, 28033
    • Adult Endocrinology and Diabetology, Hospital Ramón y Cajal
  • Málaga, Spain, 29009
    • Adult Endocrinology and Diabetology, Hospital Carlos Haya
  • Málaga, Spain, 29011
    • Pediatrics Endocrinology and Diabetology, Hospital Materno-Ifantil
  • Sevilla, Spain, 41009
    • Adult Endocrinology and Diabetology, Hospital Macarena
  • Sevilla, Spain, 41013
    • Pediatrics Endocrinology and Diabetology, Hospital Virgen del Rocío
  • Zaragoza, Spain, 50009
    • Adult and Pediatrics Endocrinology and Diabetology, Hospital Miguel Servet
• Sweden
  • Linköping, Sweden, 58185
    • Barn- och Ungdomskliniken, Universitetssjukhuset
  • Linköping, Sweden, 58185
    • Endokrinmedicinska kliniken. Universitetssjukhuset
  • Malmö, Sweden, 20502
    • Barn-och Ungdomsmedicinmottagningen and Endokrinmottagningen, Skånes Universitetssjukhus
  • Uddevalla, Sweden, 45180
    • Barn- och ungdomskliniken, Uddevalla Sjukhus
  • Uddevalla, Sweden, 45180
    • Diabetesmottagningen, Uddevalla Sjukhus
  • Umeå, Sweden, 901 85
    • Barnmottagningen, Norrlands Universitetssjukhus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 24 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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. Type 1 Diabetes (T1D) according to the Amercian Diabetes Association (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 Glutamic Acid Decarboxylase isoform 65 (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:

1. oral (except low-dose gestagen (lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives
2. combined (estrogen and progestogen containing)
3. oral, intravaginal or transdermal progesterone hormonal contraception associated with inhibition of ovulation
4. intrauterine device
5. intrauterine hormone-releasing system (for example, progestin-releasing coil)
6. bilateral tubal occlusion
7. vasectomized male (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate)
8. male partner using condom
9. abstinence from heterosexual intercourse

For males of childbearing potential:

1. condom (male)
2. abstinence from heterosexual intercourse

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. A history of anemia or significantly abnormal hematology results at screening
5. A history of epilepsy, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles
6. Clinically significant history of acute reaction to vaccines or other drugs in the past
7. 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.
8. Participation in other clinical trials with a new chemical entity within the previous 3 months
9. Inability or unwillingness to comply with the provisions of this protocol
10. A history of alcohol or drug abuse
11. A significant illness other than diabetes within 2 weeks prior to first dosing
12. Known HIV or hepatitis
13. 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)
14. 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
15. Deemed by the investigator not being able to follow instructions and/or follow the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active arm; 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)	Dietary supplement: Vitamin D; Oil suspension of Vitamin D; Biological: Diamyd; Alhydrogel®-formulated recombinant human glutamic acid decarboxylase (rhGAD65); Other Names: GAD-alum
Placebo Comparator: Placebo arm; 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)	Dietary supplement: Placebo for Vitamin D; Placebo oil suspension for Vitamin D; Biological: Placebo for Diamyd; Alhydrogel® only

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Diamyd Medical AB
• Investigators: Principal Investigator: Johnny Ludvigsson, MD, Prof, Universitetssjukhuset i Linköping

Publications and helpful links

General Publications

• Ludvigsson J, Wahlberg J, Casas R. Intralymphatic Injection of Autoantigen in Type 1 Diabetes. N Engl J Med. 2017 Feb 16;376(7):697-699. doi: 10.1056/NEJMc1616343. No abstract available. Erratum In: N Engl J Med. 2017 Jul 27;377(4):405.
• Ludvigsson J, Tavira B, Casas R. More on Intralymphatic Injection of Autoantigen in Type 1 Diabetes. N Engl J Med. 2017 Jul 27;377(4):403-5. doi: 10.1056/NEJMc1703468. No abstract available.
• Nowak C, Lind M, Sumnik Z, Pelikanova T, Nattero-Chavez L, Lundberg E, Rica I, Martinez-Brocca MA, Ruiz de Adana M, Wahlberg J, Hanas R, Hernandez C, Clemente-Leon M, Gomez-Gila A, Ferrer Lozano M, Sas T, Pruhova S, Dietrich F, Puente-Marin S, Hannelius U, Casas R, Ludvigsson J. Intralymphatic GAD-Alum (Diamyd(R)) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2. J Clin Endocrinol Metab. 2022 Aug 18;107(9):2644-2651. doi: 10.1210/clinem/dgac343.
• Ludvigsson J, Sumnik Z, Pelikanova T, Nattero Chavez L, Lundberg E, Rica I, Martinez-Brocca MA, Ruiz de Adana M, Wahlberg J, Katsarou A, Hanas R, Hernandez C, Clemente Leon M, Gomez-Gila A, Lind M, Lozano MF, Sas T, Samuelsson U, Pruhova S, Dietrich F, Puente Marin S, Nordlund A, Hannelius U, Casas R. Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial. Diabetes Care. 2021 Jul;44(7):1604-1612. doi: 10.2337/dc21-0318. Epub 2021 May 21.

Helpful Links

• Information regarding the clinical trial

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2017
• Primary Completion (Actual): July 13, 2020
• Study Completion (Actual): April 27, 2021

Study Registration Dates

• First Submitted: November 1, 2017
• First Submitted That Met QC Criteria: November 13, 2017
• First Posted (Actual): November 17, 2017

Study Record Updates

• Last Update Posted (Estimate): January 9, 2023
• Last Update Submitted That Met QC Criteria: April 11, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Diabetes; Vitamin D; Diabetes Mellitus; Micronutrients; Type 1 Diabetes Mellitus; Type 1 Diabetes; Cholecalciferol; Diamyd; Diabetes Type 1; GAD65; Diabetes Mellitus Type 1; Glucose Metabolism Disorders; Metabolic Diseases; rhGAD65; Autoimmune Diabetes; Juvenile Diabetes; Insulin Dependent Diabetes; Vitamins; Ergocalciferols
• Additional Relevant MeSH Terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Autoimmune Diseases; Endocrine System Diseases; Metabolic Diseases; Immune System Diseases; Glucose Metabolism Disorders; Physiological Effects of Drugs; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: DIAGNODE-2 (D/P2/17/6); 2017-001861-25 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No