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

• ClinicalTrials.gov Identifier: NCT03345004
• Recruitment Status: Completed
• First Posted: November 17, 2017
• Results First Posted: January 9, 2023
• Last Update Posted: January 9, 2023
• Sponsor: Diamyd Medical AB
• Information provided by (Responsible Party): Diamyd Medical AB

Tracking Information

• First Submitted Date: November 1, 2017
• First Posted Date: November 17, 2017
• Results First Submitted Date: November 23, 2021
• Results First Posted Date: January 9, 2023
• Last Update Posted Date: January 9, 2023
• Actual Study Start Date: December 20, 2017
• Actual Primary Completion Date: July 13, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 11, 2022)

Change in Stimulated C-peptide During a MMTT [ Time Frame: 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.

Original Primary Outcome Measures (submitted: November 13, 2017)

Change in stimulated C-peptide during a MMTT [ Time Frame: Baseline and 15 months ]

Change in C-peptide (Area Under the Curve [AUC]mean 0-120 min) during a Mixed Meal Tolerance Test (MMTT) between baseline to 15 months.

Current Secondary Outcome Measures (submitted: April 11, 2022)

• Change in IDAA1c [ Time Frame: Baseline and 15 months ]
  Change in insulin-dose-adjusted HbA1c (IDAA1c)
• Change in HbA1c [ Time Frame: Baseline and 15 months ]
  Change in HbA1c (mmol/mol)
• Change in Insulin Consumption [ Time Frame: Baseline and 15 months ]
  Change in daily exogenous insulin consumption (IU)
• Change in Glycemic Variability/Fluctuations [ Time Frame: 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 [ Time Frame: 15 months ]
  Percentage of patients with IDAA1c ≤ 9
• Stimulated Maximum C-peptide Above 0.2 Nmol/L [ Time Frame: 15 months ]
  Percentage of patients with a stimulated maximum C-peptide level above 0.2 nmol/L (0.6 ng/ml)
• Stimulated C-peptide Above 0.2 Nmol/L at 90 Min [ Time Frame: 15 months ]
  Percentage of patients with a stimulated 90min C-peptide level above 0.2 nmol/L (0.6 ng/ml)
• Number of Hypoglycemias [ Time Frame: 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)
• Number of Patients Having at Least 1 Severe Hypoglycemic Event [ Time Frame: Baseline and 15 months ]
  Number of patients having at least 1 severe hypoglycemic event (counts)
• Change in Maximum C-peptide [ Time Frame: Baseline and 15 months ]
  Change in maximum C-peptide during MMTT (nmol/L)
• Change in Fasting C-peptide [ Time Frame: Baseline and 15 months ]
  Change in Fasting C-peptide (nmol/L)
• C-peptide Levels During a MMTT [ Time Frame: 15 months ]
  C-peptide measured at 30, 60, 90, and 120 minutes during MMTT (nmol/L) at 15 months
• Change in Body Weight [ Time Frame: Baseline and 15 months ]
  Change in body weight (kg)
• Injection Site Reactions [ Time Frame: 15 months ]
  Injection site reactions
• Number of Clinically Significant Abnormal Results From Laboratory Measurements (Haematology and Clinical Chemistry) and Urinalysis. [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline and 15 months ]
  GAD65A titer (IU/ml)
• Number of Clinically Significant Abnormal Results in Vital Signs [ Time Frame: 15 months ]
  Vital signs (blood pressure) (mmHg)
• Change in Quality of Life (QoL) [ Time Frame: 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.
• Change in Body Mass Index (BMI) [ Time Frame: Baseline and 15 months ]
  Change in BMI (kg/m2)

Original Secondary Outcome Measures (submitted: November 13, 2017)

• Stimulated maximum C-peptide above 0.2 nmol/L [ Time Frame: 15 months ]
  • Proportion of patients with a stimulated maximum C-peptide level above 0.2 nmol/L (0.6 ng/ml)
• Stimulated C-peptide above 0.2 nmol/L at 90 min [ Time Frame: 15 months ]
  • Proportion of patients with a stimulated 90min C-peptide level above 0.2 nmol/L (0.6 ng/ml)
• • Change in maximum C-peptide [ Time Frame: Baseline and 15 months ]
  • Change in maximum C-peptide during MMTT (nmol/L)
• C-peptide levels during a MMTT [ Time Frame: 15 months ]
  • C-peptide measured at 30, 60, 90, and 120 minutes during MMTT (nmol/L) at 15 months
• • Change in Fasting C-peptide [ Time Frame: Baseline and 15 months ]
  • Change in Fasting C-peptide (nmol/L)
• Change in HbA1c [ Time Frame: Baseline and 15 months ]
  • Change in HbA1c (mmol/mol)
• Change in insulin consumption [ Time Frame: Baseline and 15 months ]
  • Change in daily exogenous insulin consumption (IU)
• Change in IDAA1c [ Time Frame: Baseline and 15 months ]
  • Change in insulin-dose-adjusted HbA1c (IDAA1c)
• Proportion of patients with IDAA1c ≤ 9 [ Time Frame: 15 months ]
  • Proportion of patients with IDAA1c ≤ 9
• Change in glycemic variability/fluctuations [ Time Frame: Screening and 15 months ]
  • Change in glycemic variability/fluctuations (evaluated from data from continuous glucose monitoring FreeStyle LibrePro, FGM) over 14 day period.
• Number of hypoglycemias [ Time Frame: 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)
• Number of patients having at least 1 severe hypoglycemic event [ Time Frame: Baseline and 15 months ]
  • Number of patients having at least 1 severe hypoglycemic event (counts)
• Change in Rate of hypoglycemic events [ Time Frame: Baseline and 15 months ]
  • Change in Rate of hypoglycemic events
• Injection site reactions [ Time Frame: 15 months ]
  • Injection site reactions
• Adverse Events [ Time Frame: 15 months ]
  • Occurrence of AEs
• Laboratory analysis of safety parameters [ Time Frame: 15 months ]
  • Laboratory measurements (hematology and clinical chemistry)
• Urine analysis [ Time Frame: 15 months ]
  • Urine analysis (microalbuminuria, creatinine)
• Physical examination [ Time Frame: 15 months ]
  • Physical examinations, including neurological assessments
• GAD65A titer [ Time Frame: 15 months ]
  • GAD65A titer (IU/ml)
• Vital signs [ Time Frame: 15 months ]
  • Vital signs (blood pressure) (mmHg)
• Total serum Immunoglobulin E [ Time Frame: 15 months ]
  • Total serum Immunoglobulin E (IgE) (IU/ml).
• Concentrations of serum autoantibodies [ Time Frame: 15 months ]
  • Concentrations of serum autoantibodies towards GAD65 and IA 2 (IU/ml).
• Concentrations of serum autoantibodies isotypes [ Time Frame: 15 months ]
  • Concentrations of serum autoantibody isotypes towards GAD65 (IU/ml).
• Cytokine secretion patterns of PBMCs [ Time Frame: 15 months ]
  • Secretion of cytokines interleukin (IL)-1, IL-2, IL-5, IL-13, IL-10, IL-17, interferon (IFN)γ, and tumour necrosis factor (TNF)α by peripheral blood mononuclear cells (PBMCs) upon stimulation with GAD65.
• Number of PMBCs secreting specific cytokines [ Time Frame: 15 months ]
  • Number of PBMCs secreting IL-10, IL-4 and/or IFNγ upon stimulation with GAD65 measured by enzyme linked immunosorbent spot forming cell assay (ELISPOT)
• Proliferation of PBMCs [ Time Frame: 15 months ]
  • Proliferation of PBMCs upon stimulation with GAD65.
• Flow cytometric analysis of PBMC subsets [ Time Frame: 15 months ]
  • FACS analysis of PBMC subsets.
• Exploratory immunological characterization [ Time Frame: 15 months ]
  • Further exploratory immunological characterization.
• Change in Quality of Life [ Time Frame: Baseline and 15 months ]
  • Change in QoL as measured by questionnaire EQ-5D-5L between baseline and Month 15.
• Quality adjusted life years [ Time Frame: 15 months ]
  • Quality adjusted life years (QALYs) based on the EQ-5D-5L questionnaire.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Diamyd Administered Into Lymph Nodes in Combination With Vitamin D in Type 1 Diabetes
• 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
• 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 Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study is a 2-arm, randomized, double-blind, placebo-controlled, multicenter, clinical trial.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

Condition

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

Intervention

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

Study Arms

• Active Comparator: Active arm
  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)
  Interventions:

  • Biological: Diamyd
  • Dietary Supplement: Vitamin D
• Placebo Comparator: Placebo arm
  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)
  Interventions:

  • Biological: Placebo for Diamyd
  • Dietary Supplement: Placebo for Vitamin D

Publications *

• 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.
• 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.
• Nowak C, Lind M, Sumnik Z, Pelikanova T, Nattero-Chavez L, Lundberg E, Rica I, Martinez-Brocca MA, Ruiz de Adana M, Wahlberg J, Hanas R, Hernandez C, Clemente-Leon M, Gomez-Gila A, Ferrer Lozano M, Sas T, Pruhova S, Dietrich F, Puente-Marin S, Hannelius U, Casas R, Ludvigsson J. Intralymphatic GAD-Alum (Diamyd(R)) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2. J Clin Endocrinol Metab. 2022 Aug 18;107(9):2644-2651. doi: 10.1210/clinem/dgac343.
• Ludvigsson J, Sumnik Z, Pelikanova T, Nattero Chavez L, Lundberg E, Rica I, Martinez-Brocca MA, Ruiz de Adana M, Wahlberg J, Katsarou A, Hanas R, Hernandez C, Clemente Leon M, Gomez-Gila A, Lind M, Lozano MF, Sas T, Samuelsson U, Pruhova S, Dietrich F, Puente Marin S, Nordlund A, Hannelius U, Casas R. Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial. Diabetes Care. 2021 Jul;44(7):1604-1612. doi: 10.2337/dc21-0318. Epub 2021 May 21.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 8, 2019): 109
• Original Estimated Enrollment (submitted: November 13, 2017): 80
• Actual Study Completion Date: April 27, 2021
• Actual Primary Completion Date: July 13, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 24 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Czechia, Netherlands, Spain, Sweden

Administrative Information

• NCT Number: NCT03345004
• Other Study ID Numbers: DIAGNODE-2 (D/P2/17/6); 2017-001861-25 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Diamyd Medical AB
• Original Responsible Party: Same as current
• Current Study Sponsor: Diamyd Medical AB
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Johnny Ludvigsson, MD, Prof; Universitetssjukhuset i Linköping

• PRS Account: Diamyd Medical AB
• Verification Date: April 2022