Open Label Trial to Evaluate the Tolerability of a Combination Therapy Consisting of GAD-alum (Diamyd®), Etanercept and Vitamin D in Children and Adolescents Newly Diagnosed With Type 1 Diabetes
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 8
- 主要终点
- Number of Patients With Reactions of the Injection Site as an Assessment of the Tolerability
研究概览
简要总结
The objectives of this study is to:
- Evaluate the tolerability of a combination therapy with Diamyd, vitamin D and etanercept
- Evaluate how the above mentioned treatments influence the immune system and endogenous insulin secretion
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 8 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed consent given by patients and parent(s)/legal guardian(s)
- •Type 1 diabetes according to the ADA classification, diagnosed within the previous 100 days at the time of screening
- •Age 8.00 -17.99 years at time of screening
- •Fasting C-peptide at time of screening ≥0.12 nmol/L
- •Positive for GADA but < 50 000 Units
- •Menarchal females must agree to avoid pregnancy and have a negative urine pregnancy test
- •Immunity against Varicella, either through previous infection or vaccination
- •Patients must follow the Swedish vaccination programme
- •Patients of childbearing potential must agree to using adequate contraception, if sexually active, until 1 year after the last administration of GAD-alum and etanercept. Adequate contraception is as follows:
- •For females of childbearing potential:
- •oral (except low-dose gestagen (lynestrenol and norethisterone), injectable, or implanted hormonal contraceptives (females)
- •intrauterine device (females)
- •intrauterine system (for example, progestin-releasing coil) (females)
- •vasectomized male (with appropriate postvasectomy documentation of the absence of sperm in the ejaculate)
- •For males of childbearing potential:
- •a. Condom (male)
排除标准
- •Previous or current treatment with immunosuppressant therapy (although topical or inhaled steroids are accepted)
- •Continuous treatment with anti-inflammatory drug (sporadic treatment e.g. because of headache or in connection with fever a few days will be accepted)
- •Treatment with any oral or injected anti-diabetic medications (especially hypoglycemic agents) other than insulin
- •Treatment with Vitamin D, marketed or not, or unwilling to abstain from such medication during the trial
- •A history of hypercalcemia
- •A history of anaemia or significantly abnormal haematology results at screening
- •A history of epilepsy, head trauma or cerebro-vascular accident, or clinical features of continuous motor unit activity in proximal muscles
- •Clinically significant history of acute reaction to vaccines or other drugs in the past
- •Treatment with any vaccine within 4 months prior to planned first administration of GAD-Alum or planned treatment with vaccine up to 4 months after the last injection with GAD-Alum, including influenza vaccine
- •Participation in other clinical trials with a new chemical entity within the previous 3 months
- •Inability or unwillingness to comply with the provisions of this protocol
- •A history of alcohol or drug abuse
- •A significant illness other than diabetes within 2 weeks prior to first dosing
- •Known human immunodeficiency virus (HIV)
- •Prior or active viral hepatitis B or C infection
- •Females who are lactating or pregnant (for females who have started menstruating the possibility of pregnancy must be excluded by urine βHCG on-site within 24 hours prior to the GAD-Alum and etanercept administration, respectively)
- •Males or females not willing to use adequate contraception, if sexually active, until 1 year after the last GAD-Alum and etanercept administration, respectively
- •Presence of associated serious disease or condition, including active skin infections that preclude subcutaneous injection, which in the opinion of the investigator makes the patient non-eligible for the study.
- •Deemed by the investigator not being able to follow instructions and/or follow the study protocol
- •Active infection, including chronic and local infection or a history of previous tendency to serious infections, recent or ongoing uncontrolled bacterial, viral, fungal or other opportunistic infections, or known infection with active EBV or CMV
- •Hypersensitivity to the active substance in Enbrel (etanercept) or other ingredients in Enbrel
- •Active or inactive (latent) tuberculosis (TBC) at screening
- •History of malignancy or significant cardiovascular disease
- •Current or history of leukopenia, anemia and/or thrombocytopenia
- •Liver disease (clinical or hepatic enzymes >3 times the upper limit of normal (ULN))
- •Renal insufficiency (clinical or creatinine >3 times the upper limit of normal (ULN))
- •MS, undefined neurologic condition or known SLE, or anti-nuclear or known doublestranded DNA antibody positivity
- •Pancreatitis
- •Vitamin D serum levels >100 nmol/L at screening
研究组 & 干预措施
A
All patients will from Day 1 receive 2 000 IU vitamin D per os per day during 15 months, and from Days 1-90 receive etanercept (Enbrel) injected subcutaneously 0.8 mg/kg body weight (max 50 mg) once a week, and receive 2 subcutaneous injections of 20 μg Diamyd in a prime-and-boost regimen on Days 30 and 60.
干预措施: GAD-Alum (Drug)
A
All patients will from Day 1 receive 2 000 IU vitamin D per os per day during 15 months, and from Days 1-90 receive etanercept (Enbrel) injected subcutaneously 0.8 mg/kg body weight (max 50 mg) once a week, and receive 2 subcutaneous injections of 20 μg Diamyd in a prime-and-boost regimen on Days 30 and 60.
干预措施: Vitamin D (Drug)
A
All patients will from Day 1 receive 2 000 IU vitamin D per os per day during 15 months, and from Days 1-90 receive etanercept (Enbrel) injected subcutaneously 0.8 mg/kg body weight (max 50 mg) once a week, and receive 2 subcutaneous injections of 20 μg Diamyd in a prime-and-boost regimen on Days 30 and 60.
干预措施: Etanercept (Drug)
结局指标
主要结局
Number of Patients With Reactions of the Injection Site as an Assessment of the Tolerability
时间窗: 2 months
Number of patients with reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching, Other). Inspection of injection site 60 minutes after GAD-Alum injection by investigator or nurse
Number of Patients With Any Abnormal Findings From Physical Examinations After Baseline
时间窗: Month 1, 2, 3, 6, 9, 15 and 30
Number of patients with any abnormal findings from physical examinations after baseline, including neurological assessments as an assessment of tolerability.
Number of Patients With Clinically Significant Laboratory Findings
时间窗: Month 1, 2, 3, 6, 9, 15 and 30
Number of patients with clinically significant laboratory findings, laboratory measurements as an assessment of the tolerability
GAD65AB Titer Measured to Evaluate the Tolerability (Main Study Period)
时间窗: 30 months
GAD65AB titer (GADA) change from baseline. GAD65AB = Antibodies to GAD with molecular mass 65000
Number of Patients With an Infection Reported as Adverse Event Related to Study Treatment
时间窗: Month 1, 2, 3, 6, 9, 15 and 30
Number of patients with an infection reported as Adverse Event related to study treatment (GAD-Alum and/or Etanercept),as an assessment of the tolerability
次要结局
- Hemoglobin A1c (HbA1c), Change From Baseline(Baseline and 30 months)
- C-peptide: Area Under the Curve (AUC 0-120 Min) During an MMTT, Change From Baseline(Baseline and 30 months at 0, 30, 60, 90 and 120 minutes post-dose)
- Number of Patients With a Stimulated Maximum C-peptide Level Above 0.2 Nmol/L(30 months)
- Spontaneous IL-17a Secretion(Baseline, 6 months, 9 months, 15 months and 30 months)
- GAD65-induced IL-4 Secretion(Baseline, 6 months, 9 months, 15 months, 30 months)
- GAD65-induced GM-CSF Secretion(Baseline, 6 months, 9 months, 15 months, 30 months)
- Exogenous Insulin Dose Per kg Body Weight and 24 Hours, Change From Baseline(Baseline and 30 months)
- C-peptide: Stimulated, 90 Minute Value, Change From Baseline(Baseline and 30 months)
- GAD65-induced IL-13 Secretion(Baseline, 6 months, 9 months, 15 months, 30 months)
- GAD65-induced IFN-gamma Secretion(Baseline, 6 months, 9 months, 15 months, 30 months)
- C-peptide Fasting Concentration, Change From Baseline(Baseline and 30 months)
- GAD65-induced MIP-1b Secretion(Baseline, 6 months, 9 months, 15 months, 30 months)
- GAD65-induced TNF-alpha Secretion(Baseline, 6 months, 9 months, 15 months, 30 months)
- GAD65-induced MCP-1 Secretion(Baseline, 6 months, 9 months, 15 months, 30 months)
研究者
Johnny Ludvigsson
MD, PhD, Professor
Linkoeping University