Clinical trial NCT02307695: The Effect of Saxagliptin on Glucose Fluctuation and Immune Regulation in Patients With Type 1 Diabetes
Official title: The Effect of Saxagliptin on Glucose Fluctuation and Immune Regulation in Patients With Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Type 1 Diabetes
Keywords: Saxagliptin
Type 1 Diabetes
Glycemic variability
C-Peptide
Lead sponsor: Nanjing Medical University
Sponsor class: OTHER
First posted: 2014-12-04
Enrollment: 184
Sex: ALL
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To investigate whether saxagliptin could reduce the fluctuation of glycemia and improve the glycemic control in those type 1 diabetes through mechanisms of suppressing glucagon secretion, improving beta cell function, and re-regulating of the T cell immune system.

Detailed description: Type 1 diabetes mellitus (T1DM) is characterized by immune mediated beta-cell destruction. Due to the imbalance between glucagon and insulin, long-term T1DM patients experience frequent hypoglycaemia and high glucose variability despite of multiple daily injections of insulin.

Dipeptidyl peptidase 4 (DPP-4) inhibitors are a new class of anti-diabetic agents and are widely used in clinical practice to improve glycemic control and protect β-cell function in patients with type 2 diabetes mellitus(T2DM). Saxagliptin, a DPP-4 inhibitor, improves glycemic control in patients with T2DM by increasing endogenous active, intact glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in response to food, which augments insulin secretion and decreases glucagon release. This mechanism can lead to the reduction of glucose variation. In some pilot studies, incretin-based therapy in patients with T1DM can improve glucose control and reduce hypoglycemia, the mechanism probably is that it regulates glucagon level. In type 1 diabetic mouse models, DPP-4 inhibitors preserves beta-cell mass and stimulating beta-cell replication.

Interestingly, DPP-4 is also known as cluster of differentiation antigen 26(CD26).It is expressed on the membrane of many types of lymphocyte, e.g. T, B and natural killer(NK)cells, and is involved in their cellular functions. CD26 plays a key role in many aspects in lymphocyte function beyond its DPP-4 enzymatic activity.These observations make it a promising therapeutic target.

Recently, the attention of saxagliptin has been mainly focused on type 2 diabetes, data in type 1 diabetes is rare. We are going to carry out this phase 4 study to testify our hypothesis that saxagliptin could reduce the fluctuation of glycemia and improve the glycemic control in those type 1 diabetes through mechanisms of suppressing glucagon secretion, improving beta cell function, and re-regulating of the T cell immune system.

Eligibility criteria: Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures;
2. Diagnosed with type 1 diabetes;
3. Men or women who are 12 to 65 years of age at time of consenting upon Visit 1.;
4. Positivity for at least one of the four islet autoantibodies(IA-2A、IAA、GADA、ZnT8A);
5. 6.5% ≤ HbA1c ≤10.0%.

Exclusion Criteria:

1. type 2 diabetes；
2. Evidence of chronic or acute complications of diabetes which is unstable and requires hospitalization；
3. Evidence of disease stress；
4. History of administration of any antihyperglycemic therapy (other than insulin) during the 12 weeks prior to Visit 1；
5. Have a history of, or currently have, acute or chronic pancreatitis；
6. Immunocompromised individuals such as patients that have undergone organ transplantation or patients diagnosed with HIV or patients with agranulocytosis；
7. Evidence of chronic or acute infection；
8. Active liver disease and/or significant abnormal liver function defined as Aspartate transaminase(AST) ≥3x Upper Limit of Normal(ULN) and/or Alanine aminotransferase (ALT) ≥3x Upper Limit of Normal(ULN)；
9. History of unstable or rapidly progressing renal disease, creatinine clearance(CrCl) ≤50ml/min;
10. Congestive heart failure defined as New York Heart Association (NYHA) class III or IV and/or left ventricular ejection fraction of ≤ 40%；
11. Rheumatoid arthritis or other autoimmune disease(except AITD);
12. Hypersensitivity to saxagliptin；
13. History of drug allergy or allergic disease
14. History of alcohol abuse, illegal drug abuse, mental disease or other disease which is not eligible for the study
15. Pregnant or breastfeeding patients；
16. Patients with any diseases which in the judgement of the investigator would compromise the patient's safety or successful participation in the clinical study
17. Any condition where, in the opinion of the investigator, participation in this study may pose a significant risk to the patient or could render the patient unable to successfully complete the study
18. Any disease or condition which the investigator feels would interfere with the trial;
19. Treatment with other immunosuppressive agent such as systemic glucocorticoids other than replacement therapy. Inhaled, local injected and topical use of glucocorticoids is allowed during the last 90 days prior to Visit 1;
20. Participation in a clinical study during the last 90 days prior to Visit 1;
21. Patients who are participating in other clinical study;
22. Treatment with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors or other contraindications to therapy as outlined in the saxagliptin package insert;
23. History of haemoglobinopathies (sickle cell anaemia or thalassemias, sideroblastic anaemia).

Primary outcomes:
measure: Change of Mean amplitude of glycemic excursions (MAGE) from baseline in patients with type 1 diabetes treated with saxagliptin plus insulin or insulin alone by continuous glucose monitoring system (CGMS)
timeFrame: 24 week
Secondary outcomes:
measure: Change of C-peptide area under the curve (AUC C-peptide) or fasting C-peptide from baseline in patients with type 1 diabetes treated with saxagliptin plus insulin or insulin alone by 3-hour mixed meal tolerance test(MMTT)
timeFrame: 24 week
measure: Change of Haemoglobin A1c (HbA1c) from baseline in patients with type 1 diabetes treated with saxagliptin plus insulin or insulin alone
timeFrame: 24 week
measure: Change of insulin dosage (U/kg/d) from baseline in patients with type 1 diabetes treated with saxagliptin plus insulin or insulin alone
timeFrame: 24 week
Other outcomes:
Locations:
city: Nanjing
country: China
facility: First Affiliated Hospital, Nanjing Medical University
state: Jiangsu
Study officials:
affiliation: First Affiliated Hospital, Nanjing Medical University, China
name: Tao Yang, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References: