Study to Explore the Effect of Dapagliflozin and Stress in Adolescent and Adult Subjects With Type 1 Diabetes (T1D)

NCT04234867 | Terminated Phase 1 DMC

• 1 other identifier: ESR-17-13152
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

Type 1 Diabetes is characterized by an absolute lack of insulin caused by autoimmune ß-cell destruction. Looking for different therapeutic approaches, beyond the administration of Insulin SGLT-Inhibitors (SGLT=sodium-glucose cotransporter) like Dapagliflozin look like a promising option to avoid hyperglycaemic excursions which are a reason for glycaemic variability by renal excretion of excessive glucose without administration of extra insulin. But also euglycemic DKA has been reported during SGLT2 add-on therapy to insulin in T1D and mechanistic studies have been called for. The role of Dapagliflozin-induced hyperglucagonemia and stress/infection precipitating euglycemic DKA in this situation is unclear. Thus the purpose of this pilot study is to collect clinical data on the development of DKA after insulin-withdrawal with Dapagliflozin compared to placebo and the added effect of a single dose of 4mg/kg i.v. ACTH as mediator of stress. The first objective is to investigate the time to DKA (defined as Bicarbonate \<19 mmol/l) after insulin withdrawal during treatment with a stable 5 day single daily dose of 10mg Dapagliflozin in patients with type 1 Diabetes. In addition it should be evaluate the additional effect of stress, modelled by a single injection of ACTH on DKA development during Dapagliflozin Treatment. We also want to know if Dapagliflozin influences glucagon levels during insulin withdrawal and how this is associated with the time course of DKA development.

Conditions

Type 1 Diabetes; Diabetic Ketoacidosis

Outcome Measures

Primary Outcomes (1)

• time to development of DKA

  time from Insulin withdrawal to development of DKA (defined as HCO3 -\< 19mmol/L)

  12 hours

Secondary Outcomes (1)

• time to decrease of ph level

  12 hours

Study Arms (4)

Dapagliflozin - Stress

EXPERIMENTAL

Administration of 10mg dapagliflozin oral for 5 days and one i.v. administration of 250µg ACTH (Synacthen)

Drug: Dapagliflozin; Other: Stress

Dapagliflozin and Placebo Stress

EXPERIMENTAL

Administration of 10mg dapagliflozin oral for 5 days and one i.v. administration of Placebo matching Synacthen

Drug: Dapagliflozin; Other: Placebo Stress

Placebo Dapagliflozin and Stress

PLACEBO COMPARATOR

Administration of placebo oral for 5 days identical to dapagliflozin and one i.v. administration of 250µg ACTH (Synacthen)

Drug: Placebo oral tablet; Other: Stress

Placebo Dapagliflozin and Placebo Stress

PLACEBO COMPARATOR

Administration of placebo oral for 5 days identical to dapagliflozin and one i.v. administration of Placebo matching Synacthen

Drug: Placebo oral tablet; Other: Placebo Stress

Interventions

Dapagliflozin DRUG

once daily for 5 days

Also known as: Forxiga

Dapagliflozin - Stress; Dapagliflozin and Placebo Stress

Placebo oral tablet DRUG

once daily for 5 days

Also known as: Control

Placebo Dapagliflozin and Placebo Stress; Placebo Dapagliflozin and Stress

Stress OTHER

single dose after last administration of experimental drug

Also known as: Synacthen

Dapagliflozin - Stress; Placebo Dapagliflozin and Stress

Placebo Stress OTHER

single dose after last administration of experimental drug

Also known as: Stress Control

Dapagliflozin and Placebo Stress; Placebo Dapagliflozin and Placebo Stress

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of informed consent from participant and all legal representatives prior to any study specific procedures
• Age: Female and/or male aged \>18 years
• Subject must have type 1 diabetes (as diagnosed clinically) ≥ 12 months
• HbA1c \<10 %
• Insulin use with an average daily dose between 0.6 - 2.0 U/kg administered by insulin pump (CSII)
• BMI 23.0 to 35.0 kg/m2 minimum weight of 50 kg
• Women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study as judged by the investigator
• WOCBP must have a negative serum pregnancy test at screening as well as negative urine tests at follow up visits
• Women must not be breastfeeding

You may not qualify if:

• History of T2DM (type 2 diabetes mellitus), maturity onset diabetes of young (MODY), pancreatic surgery or chronic pancreatitis
• Any use of oral hypoglycemic agents within 2 weeks prior to the screening visit
• History of diabetes ketoacidosis (DKA) within 12 weeks prior to prior to the screening visit
• History of diabetes insipidus
• History of hospital admission for glycemic control (either hyperglycemia or hypoglycemia) within 3 months prior to prior to the screening visit
• Frequent episodes of hypoglycemia as defined by more than one episode requiring assistance, emergency care (paramedics or emergency room care) or glucagon therapy (in children defined as seizure or loss of consciousness) , or more than 2 unexplained episodes of symptomatic hypoglycemia within 3 months prior to the screening visit.
• An unexplained event is defined as an event that cannot be explained by circumstances such as dietary (e.g. missed meal), strenuous exercise, error in insulin dosing, etc.
• Hypoglycemic unawareness
• History of Addison's disease or chronic adrenal insufficiency
• Physical and Laboratory Test Findings
• Random C-Peptide \>0.5 nmol/l
• Aspartate aminotransferase (AST) \> 2X Upper limit of normal (ULN)
• Alanine aminotransferase (ALT) \> 2X ULN
• Serum total bilirubin \> 2X ULN (except known Gilbert's disease)
• Creatine kinase (CK) \> 3X ULN

Sponsors & Collaborators

• Kinderkrankenhaus auf der Bult: lead

Study Sites (1)

Kinder- und Jugendkrankenhaus AUF DER BULT

Hanover, Lower Saxony, 30173, Germany

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetic Ketoacidosis

Interventions

dapagliflozin; adrenocorticotropin zinc

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Ketosis; Acidosis; Acid-Base Imbalance; Diabetes Complications

Study Officials

• Torben Biester, MD

  Kinderkrankenhaus auf der Bult

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 16, 2020
• First Posted: January 21, 2020
• Study Start: May 18, 2022
• Primary Completion: August 26, 2022
• Study Completion: August 26, 2022
• Last Updated: December 9, 2024

Record last verified: 2024-12

Locations

DE (1)