Clinical trial NCT03345004: Diamyd Administered Into Lymph Nodes in Combination With Vitamin D in Type 1 Diabetes
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
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
Keywords: 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
Lead sponsor: Diamyd Medical AB
Sponsor class: INDUSTRY
First posted: 2017-11-17
Enrollment: 109
Sex: ALL
Minimum age (years): 12
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study is a 2-arm, randomized, double-blind, placebo-controlled, multicenter, clinical trial.
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Change in Stimulated C-peptide During a MMTT
timeFrame: Baseline and 15 months
Secondary outcomes:
measure: Change in IDAA1c
timeFrame: Baseline and 15 months
measure: Change in HbA1c
timeFrame: Baseline and 15 months
measure: Change in Insulin Consumption
timeFrame: Baseline and 15 months
measure: Change in Glycemic Variability/Fluctuations
timeFrame: Screening and 15 months
measure: Percentage of Patients With IDAA1c ≤ 9
timeFrame: 15 months
measure: Stimulated Maximum C-peptide Above 0.2 Nmol/L
timeFrame: 15 months
measure: Stimulated C-peptide Above 0.2 Nmol/L at 90 Min
timeFrame: 15 months
measure: Number of Hypoglycemias
timeFrame: Baseline and 15 months
measure: Number of Patients Having at Least 1 Severe Hypoglycemic Event
timeFrame: Baseline and 15 months
measure: Change in Maximum C-peptide
timeFrame: Baseline and 15 months
measure: Change in Fasting C-peptide
timeFrame: Baseline and 15 months
measure: C-peptide Levels During a MMTT
timeFrame: 15 months
measure: Change in Body Weight
timeFrame: Baseline and 15 months
measure: Injection Site Reactions
timeFrame: 15 months
measure: Number of Clinically Significant Abnormal Results From Laboratory Measurements (Haematology and Clinical Chemistry) and Urinalysis.
timeFrame: 15 months
measure: Number of Clinically Significant Abnormal Results From Physical and Neurological Examinations
timeFrame: 15 months
measure: GAD65A Titer
timeFrame: Baseline and 15 months
measure: Number of Clinically Significant Abnormal Results in Vital Signs
timeFrame: 15 months
measure: Change in Quality of Life (QoL)
timeFrame: Baseline and 15 months
measure: Change in Body Mass Index (BMI)
timeFrame: Baseline and 15 months
Other outcomes:
Locations:
city: Praha
country: Czechia
facility: Diabetes Centre, Institute of Clinical and Experimental Medicine
city: Praha
country: Czechia
facility: Department of Paediatrics, University Hospital Motol
city: Rotterdam
country: Netherlands
facility: Diabeter Rotterdam
city: Barakaldo
country: Spain
facility: Adult and Pediatrics Endocrinology and Diabetology, Hospital Universitario Cruces
city: Barcelona
country: Spain
facility: Adult Endocrinology and Diabetology, Hospital vall D' Hebrón
city: Barcelona
country: Spain
facility: Pediatrics Endocrinology and Diabetology, Hospital Vall D'Hebrón
city: Madrid
country: Spain
facility: Adult Endocrinology and Diabetology, Hospital Ramón y Cajal
city: Málaga
country: Spain
facility: Adult Endocrinology and Diabetology, Hospital Carlos Haya
city: Málaga
country: Spain
facility: Pediatrics Endocrinology and Diabetology, Hospital Materno-Ifantil
city: Sevilla
country: Spain
facility: Adult Endocrinology and Diabetology, Hospital Macarena
city: Sevilla
country: Spain
facility: Pediatrics Endocrinology and Diabetology, Hospital Virgen del Rocío
city: Zaragoza
country: Spain
facility: Adult and Pediatrics Endocrinology and Diabetology, Hospital Miguel Servet
city: Linköping
country: Sweden
facility: Barn- och Ungdomskliniken, Universitetssjukhuset
city: Linköping
country: Sweden
facility: Endokrinmedicinska kliniken. Universitetssjukhuset
city: Malmö
country: Sweden
facility: Barn-och Ungdomsmedicinmottagningen and Endokrinmottagningen, Skånes Universitetssjukhus
city: Uddevalla
country: Sweden
facility: Barn- och ungdomskliniken, Uddevalla Sjukhus
city: Uddevalla
country: Sweden
facility: Diabetesmottagningen, Uddevalla Sjukhus
city: Umeå
country: Sweden
facility: Barnmottagningen, Norrlands Universitetssjukhus
Study officials:
affiliation: Universitetssjukhuset i Linköping
name: Johnny Ludvigsson, MD, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.