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

Phase 2

Completed

• Conditions: Metabolic Disease; Insulin Dependent Diabetes; Diabetes Mellitus; Endocrine System Diseases; Juvenile Diabetes; Autoimmune Diabetes; Vitamin D; Physiological Effects of Drugs; Autoimmune Diseases; Diabetes Mellitus, Type 1
• Interventions: Biological: Diamyd; Biological: Placebo for Diamyd; Dietary Supplement: Placebo for Vitamin D; Dietary Supplement: Vitamin D

• Registration Number: NCT03345004
• Lead Sponsor: Diamyd Medical AB

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.

Study Timeline

• Study First Submitted: 2017-11-01
• Study First Submitted QC: 2017-11-13
• Study First Posted: 2017-11-17
• Study Start: 2017-12-20
• Primary Completion: 2020-07-13
• Study Completion: 2021-04-27
• Results First Submitted: 2021-11-23
• Status Verified: 2022-04
• Results First Submitted QC: 2022-04-11
• Last Update Submitted: 2022-04-11
• Results First Posted: 2023-01-09
• Last Update Posted: 2023-01-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 109

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo arm	Placebo for Vitamin D	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)
Active arm	Diamyd	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)
Active arm	Vitamin D	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)
Placebo arm	Placebo for Diamyd	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)

Primary Outcome Measures

Name	Time	Method
Change in Stimulated C-peptide During a MMTT	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

Name	Time	Method
Change in IDAA1c	Baseline and 15 months	Change in insulin-dose-adjusted HbA1c (IDAA1c)
Change in HbA1c	Baseline and 15 months	Change in HbA1c (mmol/mol)
Change in Insulin Consumption	Baseline and 15 months	Change in daily exogenous insulin consumption (IU)
Change in Glycemic Variability/Fluctuations	Screening and 15 months	Change in glycemic variability/fluctuations (evaluated from data from continuous glucose monitoring FreeStyle LibrePro, FGM) over 14 day period.
Percentage of Patients With IDAA1c ≤ 9	15 months	Percentage of patients with IDAA1c ≤ 9
Stimulated C-peptide Above 0.2 Nmol/L at 90 Min	15 months	Percentage of patients with a stimulated 90min C-peptide level above 0.2 nmol/L (0.6 ng/ml)
Number of Patients Having at Least 1 Severe Hypoglycemic Event	Baseline and 15 months	Number of patients having at least 1 severe hypoglycemic event (counts)
Number of Hypoglycemias	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)
C-peptide Levels During a MMTT	15 months	C-peptide measured at 30, 60, 90, and 120 minutes during MMTT (nmol/L) at 15 months
Change in Body Weight	Baseline and 15 months	Change in body weight (kg)
Number of Clinically Significant Abnormal Results From Laboratory Measurements (Haematology and Clinical Chemistry) and Urinalysis.	15 months	Number of clinically significant abnormal results from laboratory measurements (haematology and clinical chemistry) and urinalysis. (counts)
Number of Clinically Significant Abnormal Results From Physical and Neurological Examinations	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"
GAD65A Titer	Baseline and 15 months	GAD65A titer (IU/ml)
Stimulated Maximum C-peptide Above 0.2 Nmol/L	15 months	Percentage of patients with a stimulated maximum C-peptide level above 0.2 nmol/L (0.6 ng/ml)
Change in Maximum C-peptide	Baseline and 15 months	Change in maximum C-peptide during MMTT (nmol/L)
Change in Fasting C-peptide	Baseline and 15 months	Change in Fasting C-peptide (nmol/L)
Number of Clinically Significant Abnormal Results in Vital Signs	15 months	Vital signs (blood pressure) (mmHg)
Change in Body Mass Index (BMI)	Baseline and 15 months	Change in BMI (kg/m2)
Injection Site Reactions	15 months	Injection site reactions
Change in Quality of Life (QoL)	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.

Trial Locations

Locations (18)

Pediatrics Endocrinology and Diabetology, Hospital Vall D'Hebrón; 🇪🇸 Barcelona, Spain

Adult Endocrinology and Diabetology, Hospital Carlos Haya; 🇪🇸 Málaga, Spain

Adult and Pediatrics Endocrinology and Diabetology, Hospital Universitario Cruces; 🇪🇸 Barakaldo, Spain

Barn- och ungdomskliniken, Uddevalla Sjukhus; 🇸🇪 Uddevalla, Sweden

Pediatrics Endocrinology and Diabetology, Hospital Virgen del Rocío; 🇪🇸 Sevilla, Spain

Diabetesmottagningen, Uddevalla Sjukhus; 🇸🇪 Uddevalla, Sweden

Barn- och Ungdomskliniken, Universitetssjukhuset; 🇸🇪 Linköping, Sweden

Barn-och Ungdomsmedicinmottagningen and Endokrinmottagningen, Skånes Universitetssjukhus; 🇸🇪 Malmö, Sweden

Barnmottagningen, Norrlands Universitetssjukhus; 🇸🇪 Umeå, Sweden

Diabetes Centre, Institute of Clinical and Experimental Medicine; 🇨🇿 Praha, Czechia

Diabeter Rotterdam; 🇳🇱 Rotterdam, Netherlands

Department of Paediatrics, University Hospital Motol; 🇨🇿 Praha, Czechia

Adult Endocrinology and Diabetology, Hospital vall D' Hebrón; 🇪🇸 Barcelona, Spain

Endokrinmedicinska kliniken. Universitetssjukhuset; 🇸🇪 Linköping, Sweden

Adult and Pediatrics Endocrinology and Diabetology, Hospital Miguel Servet; 🇪🇸 Zaragoza, Spain

Adult Endocrinology and Diabetology, Hospital Ramón y Cajal; 🇪🇸 Madrid, Spain

Pediatrics Endocrinology and Diabetology, Hospital Materno-Ifantil; 🇪🇸 Málaga, Spain

Adult Endocrinology and Diabetology, Hospital Macarena; 🇪🇸 Sevilla, Spain