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

• ClinicalTrials.gov Identifier: NCT03345004
• Recruitment Status: Completed
• First Posted: November 17, 2017
• Results First Posted: January 9, 2023
• Last Update Posted: January 9, 2023
• Sponsor: Diamyd Medical AB
• Information provided by (Responsible Party): Diamyd Medical AB

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
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	Biological: Diamyd; Dietary Supplement: Vitamin D; Biological: Placebo for Diamyd; Dietary Supplement: Placebo for Vitamin D	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 109 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The study is a 2-arm, randomized, double-blind, placebo-controlled, multicenter, clinical trial.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: December 20, 2017
• Actual Primary Completion Date: July 13, 2020
• Actual Study Completion Date: April 27, 2021

Arms and Interventions

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)	Biological: Diamyd; Alhydrogel®-formulated recombinant human glutamic acid decarboxylase (rhGAD65); Other Name: GAD-alum; Dietary Supplement: Vitamin D; Oil suspension of Vitamin D
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)	Biological: Placebo for Diamyd; Alhydrogel® only; Dietary Supplement: Placebo for Vitamin D; Placebo oil suspension for Vitamin D

Outcome Measures

Primary Outcome Measures :

1. Change in Stimulated C-peptide During a MMTT [ Time Frame: Baseline and 15 months ]
   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.

Secondary Outcome Measures :

1. Change in IDAA1c [ Time Frame: Baseline and 15 months ]
   Change in insulin-dose-adjusted HbA1c (IDAA1c)
2. Change in HbA1c [ Time Frame: Baseline and 15 months ]
   Change in HbA1c (mmol/mol)
3. Change in Insulin Consumption [ Time Frame: Baseline and 15 months ]
   Change in daily exogenous insulin consumption (IU)
4. Change in Glycemic Variability/Fluctuations [ Time Frame: Screening and 15 months ]
   Change in glycemic variability/fluctuations (evaluated from data from continuous glucose monitoring FreeStyle LibrePro, FGM) over 14 day period.
5. Percentage of Patients With IDAA1c ≤ 9 [ Time Frame: 15 months ]
   Percentage of patients with IDAA1c ≤ 9
6. Stimulated Maximum C-peptide Above 0.2 Nmol/L [ Time Frame: 15 months ]
   Percentage of patients with a stimulated maximum C-peptide level above 0.2 nmol/L (0.6 ng/ml)
7. Stimulated C-peptide Above 0.2 Nmol/L at 90 Min [ Time Frame: 15 months ]
   Percentage of patients with a stimulated 90min C-peptide level above 0.2 nmol/L (0.6 ng/ml)
8. Number of Hypoglycemias [ Time Frame: Baseline and 15 months ]
   Number of self-reported episodes of severe hypoglycemia (Severe hypoglycemia defined as needing help from others and/or seizures and/or unconscious) (counts)
9. Number of Patients Having at Least 1 Severe Hypoglycemic Event [ Time Frame: Baseline and 15 months ]
   Number of patients having at least 1 severe hypoglycemic event (counts)
10. Change in Maximum C-peptide [ Time Frame: Baseline and 15 months ]
    Change in maximum C-peptide during MMTT (nmol/L)
11. Change in Fasting C-peptide [ Time Frame: Baseline and 15 months ]
    Change in Fasting C-peptide (nmol/L)
12. C-peptide Levels During a MMTT [ Time Frame: 15 months ]
    C-peptide measured at 30, 60, 90, and 120 minutes during MMTT (nmol/L) at 15 months
13. Change in Body Weight [ Time Frame: Baseline and 15 months ]
    Change in body weight (kg)
14. Injection Site Reactions [ Time Frame: 15 months ]
    Injection site reactions
15. Number of Clinically Significant Abnormal Results From Laboratory Measurements (Haematology and Clinical Chemistry) and Urinalysis. [ Time Frame: 15 months ]
    Number of clinically significant abnormal results from laboratory measurements (haematology and clinical chemistry) and urinalysis. (counts)
16. Number of Clinically Significant Abnormal Results From Physical and Neurological Examinations [ Time Frame: 15 months ]

    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"

17. GAD65A Titer [ Time Frame: Baseline and 15 months ]
    GAD65A titer (IU/ml)
18. Number of Clinically Significant Abnormal Results in Vital Signs [ Time Frame: 15 months ]
    Vital signs (blood pressure) (mmHg)
19. Change in Quality of Life (QoL) [ Time Frame: Baseline and 15 months ]
    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.
20. Change in Body Mass Index (BMI) [ Time Frame: Baseline and 15 months ]
    Change in BMI (kg/m2)

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Czechia

Diabetes Centre, Institute of Clinical and Experimental Medicine

Praha, Czechia, 14021

Department of Paediatrics, University Hospital Motol

Praha, Czechia, 15006

Netherlands

Diabeter Rotterdam

Rotterdam, Netherlands, 3011 TA

Spain

Adult and Pediatrics Endocrinology and Diabetology, Hospital Universitario Cruces

Barakaldo, Spain, 48903

Adult Endocrinology and Diabetology, Hospital vall D' Hebrón

Barcelona, Spain, 08035

Pediatrics Endocrinology and Diabetology, Hospital Vall D'Hebrón

Barcelona, Spain, 08035

Adult Endocrinology and Diabetology, Hospital Ramón y Cajal

Madrid, Spain, 28033

Adult Endocrinology and Diabetology, Hospital Carlos Haya

Málaga, Spain, 29009

Pediatrics Endocrinology and Diabetology, Hospital Materno-Ifantil

Málaga, Spain, 29011

Adult Endocrinology and Diabetology, Hospital Macarena

Sevilla, Spain, 41009

Pediatrics Endocrinology and Diabetology, Hospital Virgen del Rocío

Sevilla, Spain, 41013

Adult and Pediatrics Endocrinology and Diabetology, Hospital Miguel Servet

Zaragoza, Spain, 50009

Sweden

Barn- och Ungdomskliniken, Universitetssjukhuset

Linköping, Sweden, 58185

Endokrinmedicinska kliniken. Universitetssjukhuset

Linköping, Sweden, 58185

Barn-och Ungdomsmedicinmottagningen and Endokrinmottagningen, Skånes Universitetssjukhus

Malmö, Sweden, 20502

Barn- och ungdomskliniken, Uddevalla Sjukhus

Uddevalla, Sweden, 45180

Diabetesmottagningen, Uddevalla Sjukhus

Uddevalla, Sweden, 45180

Barnmottagningen, Norrlands Universitetssjukhus

Umeå, Sweden, 901 85

Sponsors and Collaborators

Diamyd Medical AB

Investigators

• Principal Investigator: Johnny Ludvigsson, MD, Prof; Universitetssjukhuset i Linköping

  Study Documents (Full-Text)

Documents provided by Diamyd Medical AB:

Study Protocol  [PDF] May 15, 2020

Statistical Analysis Plan  [PDF] June 23, 2020

More Information

Additional Information:

Information regarding the clinical trial 

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Diamyd Medical AB
• ClinicalTrials.gov Identifier: NCT03345004
• Other Study ID Numbers: DIAGNODE-2 (D/P2/17/6); 2017-001861-25 ( EudraCT Number )
• First Posted: November 17, 2017
• Results First Posted: January 9, 2023
• Last Update Posted: January 9, 2023
• Last Verified: April 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Diamyd Medical AB:

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

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Metabolic Diseases; Glucose Metabolism Disorders; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents