Clinical trial NCT04262479: Injections of Glutamic Acid Decarboxylase (GAD) for LADA Type of Diabetes
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Latent Autoimmune Diabetes in Adults
Keywords: Glutamic Acid Decarboxylase
Alum Compounds
Injections
Inguinal Canal
Diamyd
rhGAD65
Vitamin D
Lead sponsor: Norwegian University of Science and Technology
Sponsor class: OTHER
Collaborators: name: St. Olavs Hospital
name: Diamyd Medical AB
name: Karolinska Institutet
name: Linkoeping University
First posted: 2020-02-10
Enrollment: 14
Sex: ALL
Minimum age (years): 30
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: The purpose of the trial is to evaluate the effects of 3 intra-nodal injections of GAD-alum, together with oral vitamin D supplementation, in a population of LADA patients with high GADA titers. Effects will be summarized at 5 and 12 months after the first injection.

* The primary objective is to evaluate safety and feasibility of this treatment regimen.
* Secondary objectives are to test if the treatment induces a strong GAD-specific immune response similar to what has previously been observed in type 1 diabetes patients and to test for indications of preservation of endogenous insulin production.

The study is an open label Phase IIa feasibility trial. It is a pilot study that does not include a placebo arm.

Antidiabetic medication in the form of metformin is acceptable before and during the trial. Study participants must be insulin independent at baseline, but if the need for insulin treatment develops during the trial, such treatment will be given.

GAD-alum will be injected directly into an inguinal lymph node by a qualified radiologist.

Patients will be followed for a total of 12 months during which their endogenous insulin production and immune response will be evaluated at regular intervals throughout the study period. Urine and blood samples will be taken for safety, diabetes status assessments, vitamin D levels and immunological assessments. Concomitant medication and demographics will be collected.

Eligibility 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 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)

Primary outcomes:
measure: Injection Site Skin Reactions
timeFrame: 1 hour
measure: Occurrence of Adverse Events (AEs) During 5 Months From Baseline.
timeFrame: From baseline (first injection of GAD-alum) to 5 months after baseline.
measure: Occurrence of Adverse Events (AEs) During the Study.
timeFrame: From baseline (first injection of GAD-alum) to 12 months after baseline.
measure: Serum GAD65A Titers, Change From Baseline at 5 Months After Baseline.
timeFrame: Baseline (first injection of GAD-alum) and 5 months after baseline.
measure: Serum GAD65A Titers, Change From Baseline at 12 Months After Baseline.
timeFrame: Baseline and 12 months after baseline.
measure: Serum GAD65A Titers, Change From Baseline at 12 Months After Baseline.
timeFrame: Baseline (first injection of GAD-alum) and 12 months after baseline.
Secondary outcomes:
measure: Insulin Secretion, Change From Baseline to 5 Months After Baseline.
timeFrame: Baseline (first injection of GAD-alum) and 5 months after baseline.
measure: Insulin Secretion, Change From Baseline to 12 Months After Baseline.
timeFrame: Baseline (first injection of GAD-alum) and 12 months after baseline.
measure: Change in HbA1c
timeFrame: from baseline to 12 months after the first injection
measure: Change in Fasting Glucose
timeFrame: From baseline to 12 months after the first injection
measure: Change in Fasting C-peptide
timeFrame: Between baseline and 12 months after the first injection
measure: Change in Maximum C-peptide During Mixed Meal Tolerance Test (MMTT)
timeFrame: between baseline 12 months after the first injection
Other outcomes:
Locations:
city: Trondheim
country: Norway
facility: Department of Endocrinology, St Olavs Hospital
city: Stockholm
country: Sweden
facility: Akademiskt Specialistcentrum, Centrum for Diabetes, and Karolinska Institute
Study officials:
affiliation: St Olavs Hospital, Medisinsk Klinikk
name: Anne Hildur Henriksen, MD PhD
role: STUDY_DIRECTOR
affiliation: Norwegian University of Science and Technology, IKOM
name: Torstein Baade Rø, MD
role: STUDY_DIRECTOR
References:
citation: 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.