Injections of Glutamic Acid Decarboxylase (GAD) for LADA Type of Diabetes (GADinLADA)

A Pilot Study on Safety, Feasibility and Insulin-promotion by Intra-inguinal Lymph Node Injections of Glutamic Acid Decarboxylase (GAD) in Patients With LADA Type of Diabetes

This study will evaluate the effects of 3 intra-nodal injections of GAD-alum (Diamyd), together with oral vitamin D supplementation. Safety and feasibility of the treatment will be evaluated and also effects on the immune system and on the preservation of endogenous insulin production.

Study Overview

• Status: Completed
• Conditions: Latent Autoimmune Diabetes in Adults
• Intervention / Treatment: Drug: recombinant human glutamic acid dehydrogenase (rhGAD65), formulated in aluminium hydrogel; Drug: Vitamin D

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Trondheim, Norway
    • Department of Endocrinology, St Olavs Hospital
• Sweden
  • Stockholm, Sweden
    • Akademiskt Specialistcentrum, Centrum for Diabetes, and Karolinska Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed informed consent by the patient.
2. Diagnosis of LADA and diabetes debut within the last 18 months before inclusion. LADA should be defined by the criteria of age ≥30 years at the onset of diabetes, anti-GAD positivity and no clinical need for permanent insulin treatment during the first 3 months after the diagnosis of diabetes.
3. Fasting C-peptid levels ≥ 0.3 nmol/l
4. High GADA titers (>190 U/ml)
5. Patients must be insulin independent at baseline by clinical judgement and C-peptide criteria
6. Antidiabetic medication in the form of metformin is acceptable for inclusion as well as medications not mentioned under exclusion criteria
7. Females must agree to avoid pregnancy, and must 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 GAD-alum. 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. Current or previous treatment with immunosuppressant therapy (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. Systemic treatment with glucocorticoids
4. Treatment with any vaccine, including influenza vaccine, within 1 month prior to planned first study drug dose or planned treatment with any vaccine up to 1 month after the last injection with study drug
5. Antidiabetic medication (metformin excepted)
6. Significantly abnormal hematology results at screening (i.e. anemia with hemoglobin < 12 g/L).
7. A history of epilepsy, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles
8. Clinically significant history of acute reaction to vaccines in the past.
9. Renal disease (as defined by serum creatinine >150 µmol/l)
10. Serious cardiovascular events (myocardial infarction, stroke) within the last year preceding recruitment.
11. Participation in other clinical trials with a new chemical entity within the previous 3 months
12. A history of alcohol or drug abuse
13. Known HIV or hepatitis
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. Other serious chronic disease as judged by investigator.
16. Females who are lactating, are pregnant or intend to become pregnant.
17. Inability or unwillingness to comply with the provisions of this protocol
18. Deemed by the investigator not being able to follow instructions and/or follow the study protocol
19. Treatment any other supplementation of with vitamin D, marketed or not, or unwilling to abstain from such medication during the trial 120 days daily intake of Divisun (non-investigational medicinal product)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: GAD-vaccination with vitamin D suppletion; Each study participant will receive 3 injections of 4 µg GAD-alum (Diamyd). The first, second and third injection will be one month apart. Vitamin D (Divisun 2000 IE) will be given from one month before the first injection of GAD-alum until one month after the third injection (120 days in total).

Drug: recombinant human glutamic acid dehydrogenase (rhGAD65), formulated in aluminium hydrogel; 3 intra-inguinal injections (into the lymph nodes) of GAD-alum one month apart. Supplier Diamyd Medical AB in Stockholm, Sweden; Other Names: GAD-alum (Diamyd(R)); Drug: Vitamin D; 1 tablet/day, total daily dose of 2000 IE given per os from day -30 through day 90. Supplier Meda, Solna, Sweden; Other Names: Divisun 2000 IE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
injection site skin reactions	skin reactions 1 hour post injection vs. before injection	1 hour
Occurrence of adverse events (AEs)	continuously monitored and registered	summarized at 5 months
Occurrence of adverse events (AEs)	continuously monitored and registered	summarized at 12 months
GAD65A titer in serum	concentration in serum after the first injection vs baseline	at 5 months
GAD65A titer in serum	concentration in serum after the first injection vs baseline	at 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin secretion	measured by glucagon- and MMTT stimulated C-peptide	5 months after first injection
insulin secretion	measured by glucagon- and MMTT stimulated C-peptide	12 months after first injection
Change in HbA1c		from baseline to 5 and 12 months after the first injection
Change in fasting glucose		from baseline to 5 and 12 months after the first injection
Change in Fasting C-peptide		between baseline and 5 and 12 months after the first injection
Change in maximum C-peptide during Mixed Meal Tolerance Test (MMTT)		between baseline and 5 and 12 months after the first injection

Collaborators and Investigators

• Sponsor: Norwegian University of Science and Technology
• Collaborators: Karolinska Institutet; Linkoeping University; St. Olavs Hospital; Diamyd Medical AB
• Investigators: Study Director: Anne Hildur Henriksen, MD PhD, St Olavs Hospital, Medisinsk Klinikk; Study Director: Torstein Baade Rø, MD, Norwegian University of Science and Technology, IKOM

Publications and helpful links

General Publications

• Hals IK, Fiskvik Fleiner H, Reimers N, Astor MC, Filipsson K, Ma Z, Grill V, Bjorklund A. Investigating optimal beta-cell-preserving treatment in latent autoimmune diabetes in adults: Results from a 21-month randomized trial. Diabetes Obes Metab. 2019 Oct;21(10):2219-2227. doi: 10.1111/dom.13797. Epub 2019 Jun 19.

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2020
• Primary Completion (Actual): May 5, 2022
• Study Completion (Actual): May 5, 2022

Study Registration Dates

• First Submitted: February 5, 2020
• First Submitted That Met QC Criteria: February 6, 2020
• First Posted (Actual): February 10, 2020

Study Record Updates

• Last Update Posted (Actual): May 26, 2022
• Last Update Submitted That Met QC Criteria: May 25, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Vitamin D; Injections; Diamyd; Glutamic Acid Decarboxylase; Alum Compounds; Inguinal Canal; rhGAD65
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Latent Autoimmune Diabetes in Adults; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Vitamin D
• Other Study ID Numbers: GADinLADA; 2019-002692-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: There is not a plan to make IPD available.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No