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

Diabetes Mellitus Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03345004
• Other study ID #: DIAGNODE-2 (D/P2/17/6)
• Secondary ID: 2017-001861-25
• Status: Completed
• Phase: Phase 2
• Start date: December 20, 2017
• Est. completion date: April 27, 2021

Study information

• Verified date: April 2022
• Source: Diamyd Medical AB
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 109
• Est. completion date: April 27, 2021
• Est. primary completion date: July 13, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 24 Years

Eligibility

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 ßHCG 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

Related Conditions & MeSH terms

• Autoimmune Diabetes
• Autoimmune Diseases
• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Endocrine System Diseases
• Glucose Metabolism Disorders
• Immune System Diseases
• Insulin Dependent Diabetes
• Juvenile Diabetes
• Metabolic Disease
• Metabolic Diseases
• Physiological Effects of Drugs
• Vitamin D

Intervention

Biological:
• Diamyd
Alhydrogel®-formulated recombinant human glutamic acid decarboxylase (rhGAD65)

Dietary Supplement:
• Vitamin D
Oil suspension of Vitamin D

Biological:
• Placebo for Diamyd
Alhydrogel® only

Dietary Supplement:
• Placebo for Vitamin D
Placebo oil suspension for Vitamin D

Locations

Country	Name	City	State
Czechia	Department of Paediatrics, University Hospital Motol	Praha
Czechia	Diabetes Centre, Institute of Clinical and Experimental Medicine	Praha
Netherlands	Diabeter Rotterdam	Rotterdam
Spain	Adult and Pediatrics Endocrinology and Diabetology, Hospital Universitario Cruces	Barakaldo
Spain	Adult Endocrinology and Diabetology, Hospital vall D' Hebrón	Barcelona
Spain	Pediatrics Endocrinology and Diabetology, Hospital Vall D'Hebrón	Barcelona
Spain	Adult Endocrinology and Diabetology, Hospital Ramón y Cajal	Madrid
Spain	Adult Endocrinology and Diabetology, Hospital Carlos Haya	Málaga
Spain	Pediatrics Endocrinology and Diabetology, Hospital Materno-Ifantil	Málaga
Spain	Adult Endocrinology and Diabetology, Hospital Macarena	Sevilla
Spain	Pediatrics Endocrinology and Diabetology, Hospital Virgen del Rocío	Sevilla
Spain	Adult and Pediatrics Endocrinology and Diabetology, Hospital Miguel Servet	Zaragoza
Sweden	Barn- och Ungdomskliniken, Universitetssjukhuset	Linköping
Sweden	Endokrinmedicinska kliniken. Universitetssjukhuset	Linköping
Sweden	Barn-och Ungdomsmedicinmottagningen and Endokrinmottagningen, Skånes Universitetssjukhus	Malmö
Sweden	Barn- och ungdomskliniken, Uddevalla Sjukhus	Uddevalla
Sweden	Diabetesmottagningen, Uddevalla Sjukhus	Uddevalla
Sweden	Barnmottagningen, Norrlands Universitetssjukhus	Umeå

Sponsors (1)

Lead Sponsor	Collaborator
Diamyd Medical AB

Countries where clinical trial is conducted

Czechia,  Netherlands,  Spain,  Sweden, 

References & Publications (2)

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. — View 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. Erratum In: N Engl J Med. 2017 Jul 27;377(4):405. — View Citation

Outcome

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

External Links

•   Information regarding the clinical trial