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

• ClinicalTrials.gov Identifier: NCT04262479
• Recruitment Status: Recruiting
• First Posted: February 10, 2020
• Last Update Posted: November 4, 2020
• Sponsor: Norwegian University of Science and Technology
• Collaborators: St. Olavs Hospital; Diamyd Medical AB; Karolinska University Hospital; Linkoeping University
• Information provided by (Responsible Party): Norwegian University of Science and Technology

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Latent Autoimmune Diabetes in Adults	Drug: recombinant human glutamic acid dehydrogenase (rhGAD65), formulated in aluminium hydrogel; Drug: Vitamin D	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 2, 2020
• Estimated Primary Completion Date: June 2022
• Estimated Study Completion Date: June 2022

Arms and Interventions

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 Name: 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 Name: Divisun 2000 IE

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Insulin secretion [ Time Frame: 5 months after first injection ]
   measured by glucagon- and MMTT stimulated C-peptide
2. insulin secretion [ Time Frame: 12 months after first injection ]
   measured by glucagon- and MMTT stimulated C-peptide
3. Change in HbA1c [ Time Frame: from baseline to 5 and 12 months after the first injection ]
4. Change in fasting glucose [ Time Frame: from baseline to 5 and 12 months after the first injection ]
5. Change in Fasting C-peptide [ Time Frame: between baseline and 5 and 12 months after the first injection ]
6. Change in maximum C-peptide during Mixed Meal Tolerance Test (MMTT) [ Time Frame: between baseline and 5 and 12 months after the first injection ]

Eligibility Criteria

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

Criteria

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 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
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 with vitamin D, marketed or not, or unwilling to abstain from such medication during the trial

Contacts and Locations

Contacts

Contact: Ingrid Kathrin Hals, PhD; +47 73412207; ingrid.hals@ntnu.no

Contact: Chandima Balasuriya, MD PhD; 72829705; chandima.nirupa.dilruks.balasuriya@stolav.no

Locations

Norway

Department of Endocrinology, St Olavs Hospital; Recruiting

Trondheim, Norway

Contact: Chandima Balasuriya, MD PhD +47 72829705 chandima.nirupa.dilruks.balasuriya@stolav.no

Sweden

Akademiskt Specialistcentrum, Centrum for Diabetes, and Karolinska University Hospital; Recruiting

Stockholm, Sweden

Contact: Anneli Björklund, MD PhD

Sponsors and Collaborators

Norwegian University of Science and Technology

St. Olavs Hospital

Diamyd Medical AB

Karolinska University Hospital

Linkoeping University

Investigators

• Study Director: Tom Christian Martinsen, MD PhD; St Olavs Hospital, Medisinsk Klinikk
• Study Director: Torstein Baade Rø, MD; Norwegian University of Science and Technology, IKOM

More Information

Publications:

Hals IK, Fiskvik Fleiner H, Reimers N, Astor MC, Filipsson K, Ma Z, Grill V, Björklund A. Investigating optimal β-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.

• Responsible Party: Norwegian University of Science and Technology
• ClinicalTrials.gov Identifier: NCT04262479
• Other Study ID Numbers: GADinLADA; 2019-002692-34 ( EudraCT Number )
• First Posted: February 10, 2020
• Last Update Posted: November 4, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: There is not a plan to make IPD available.

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

Keywords provided by Norwegian University of Science and Technology:

Glutamic Acid Decarboxylase; Alum Compounds; Injections; Inguinal Canal; Diamyd; rhGAD65; Vitamin D

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Latent Autoimmune Diabetes in Adults; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Vitamin D; Vitamins; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs; Bone Density Conservation Agents