E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012601 |
E.1.2 | Term | Diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to evaluate the efficacy of Diamyd, administered into lymph nodes in combination with an oral vitamin D regimen, compared to placebo in terms of preserving endogenous insulin secretion as measured by C-peptide. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to compare Diamyd, administered into lymph nodes in combination with an oral vitamin D regimen and placebo treatment with respect to the effects on the diabetes status, treatment safety, immune system and quality of life (QoL) of the patients. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. T1D according to the 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 5. Positive for 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: a. oral (except low‐dose gestagen (lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives b. combined (estrogen and progestogen containing) c. oral, intravaginal or transdermal progesterone hormonal contraception associated with inhibition of ovulation d. intrauterine device e. intrauterine hormone-releasing system (for example, progestin‐releasing coil) f. bilateral tubal occlusion g. vasectomized male (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate) h. male partner using condom i. abstinence from heterosexual intercourse
For males of childbearing potential: a. condom (male) b. abstinence from heterosexual intercourse |
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E.4 | Principal 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. Treatment with Vitamin D, marketed or not, or unwilling to abstain from such medication during the trial 5. A history of anemia or significantly abnormal hematology results at screening 6. A history of epilepsy, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles 7. Clinically significant history of acute reaction to vaccines or other drugs in the past 8. 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. 9. Participation in other clinical trials with a new chemical entity within the previous 3 months 10. Inability or unwillingness to comply with the provisions of this protocol 11. A history of alcohol or drug abuse 12. A significant illness other than diabetes within 2 weeks prior to first dosing 13. Known HIV or hepatitis 14. 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) 15. 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 16. Deemed by the investigator not being able to follow instructions and/or follow the study protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
• 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
between baseline to 15 months |
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E.5.2 | Secondary end point(s) |
The key secondary endpoints to evaluate diabetic status are: •Change in insulin-dose-adjusted HbA1c (IDAA1c) between baseline and 15 months. •Change in HbA1c between baseline and 15 months. •Change in daily exogenous insulin consumption between baseline and 15 months. The other secondary endpoints to evaluate diabetic status are: •Change in glycemic variability/fluctuations (evaluated from data from continuous glucose monitoring FreeStyle LibrePro, Flash Glucose Monitoring [FGM]) over 14 day period between Screening and 15 months. •Proportion of patients with IDAA1c ≤ 9 at 15 months. • Proportion of patients with a stimulated maximum C-peptide level above 0.2 nmol/L at 15 months. • Proportion of patients with a stimulated 90min C-peptide level above 0.2 nmol/L at 15 months. •Number of self-reported episodes of severe hypoglycemia (Severe hypoglycemia defined as needing help from others and/or seizures and/or unconscious) between baseline and 15 months •Change in Rate of hypoglycemic events between baseline and 15 months. •Number of patients having at least 1 severe hypoglycemic event between baseline and 15 months • Change in maximum C-peptide during MMTT between baseline and 15 months. •Change in Fasting C-peptide between baseline and 15 months. • C-peptide measured at 30, 60, 90, es during MMTT at 15 months. •Change in body weight and body mass index (BMI) between baseline and 15 months
The secondary endpoints to evaluate safety are: • Injection site reactions • Occurrence of AEs • Laboratory measurements (hematology and clinical chemistry) • Urinalysis (microalbuminuria, creatinine) • Physical examinations, including neurological assessments • GAD65A titer • Vital signs (blood pressure)
The secondary endpoints to evaluate the influence on the immune system are: • Concentrations of serum autoantibodies towards GAD65 and IA • Concentrations of serum autoantibody isotypes towards GAD65. • 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. •Serum concentrations of cytokines IL-1, IL-2, IL-5, IL-13, IL-10, IL-17, IFNγ, and TNFα. •Secretion of cytokines IL-1, IL-2, IL-5, IL-13, IL-10, IL-17, IFNγ, and TNFα by PBMCs upon stimulation with anti-CD3 and anti-CD28. • Proliferation of PBMCs upon stimulation with GAD65. • Further exploratory immunological characterization.
The secondary endpoints of Quality of Life are: • Change in QoL as measured by questionnaire EQ-5D-5L between baseline and Month 15. • Quality adjusted life years (QALYs) based on the EQ-5D-5L questionnaire.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
between baseline to 15 months |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |