Dapagliflozin During Exercise for the PrevenTion of Hypoglycaemia

NCT03537131 | Terminated Phase 2 DMC

• 2 other identifiers: 230920172017-003911-21
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

There are approximately 400,000 people in the UK who are living with type 1 diabetes (T1DM), of whom 29,000 are children. People with T1DM experience on average 2 episodes of symptomatic hypoglycaemia per week , and exercise (especially aerobic) increases this risk . Strategies to prevent hypoglycaemia during and after exercise include increasing glucose consumption and reducing insulin dose, however overcompensation may result in worsening of blood glucose control. Dysregulated glucagon secretion, manifested as a reduced counter-regulatory response during hypoglycaemia, is a key feature in T1DM, occurring soon after diagnosis. Anecdotal evidence suggests that SGLT-2 (sodium/glucose cotransporter-2) inhibitors (SGLT2i) such as dapagliflozin prevent exercise-induced hypoglycaemia in T1DM. SGLT2is promote glucose excretion without causing hypoglycaemia.Paradoxically, given their mode of action, they increase plasma glucose and stimulate glucagon secretion. Studies in diabetic rats indicate that the physiological counter-regulatory response is suppressed in insulin-treated diabetes, a defect that can be corrected by somatostatin antagonists. The DEPTH trial will test the novel hypothesis that hypoglycaemia results from hypersecretion of somatostatin, and that this defect can be corrected by SGLT2i. As these medications are already in clinical use, our findings may be rapidly translated into practice. Understanding these key processes has the potential to generate novel therapeutic strategies to improve glycaemic control, thereby facilitating a more active lifestyle in people with T1DM.

Conditions

Diabetes Mellitus, Type 1

Keywords

diabetes; dapagliflozin; exercise; hypoglycemia

Outcome Measures

Primary Outcomes (1)

• Time to hypoglycaemia during the exercise challenge, before and after dapagliflozin treatment.

  To determine whether dapagliflozin (either regular or as a single dose) can delay/prevent the onset of hypoglycaemia during moderate intensity exercise. Following blood glucose stabilisation at 5mmol/L (90mg/dL) during the euglycaemic clamp, participants will begin exercising at moderate intensity (50-60% VO2 max) for up to 90min. Time to hypoglycaemia (defined as blood glucose \<3.3mmol/L, 60mg/dL) will be determined before (Part A) and after (Part B) dapagliflozin treatment.

  90min exercise challenge during Part A and Part B

Secondary Outcomes (3)

• Duration of time in hypoglycaemia following the exercise challenge, before and after dapagliflozin treatment.

  24-hour period after each exercise challenge

• Concentration of plasma glucose, glucagon and somatostatin-14 at each 10min interval during the exercise challenge.

  Every 10min during the 90min exercise challenge during Part A and Part B

• Concentration of plasma potassium, sodium, calcium and pH at each 10min interval during exercise challenge

  Every 10min during the 90min exercise challenge during Part A and Part B

Study Arms (2)

arm B1- Dapagliflozin once only dose

ACTIVE COMPARATOR

Participants who will take one tablet of Dapagliflozin 10 mg on the day of the exercise challenge.

Drug: Dapagliflozin 10 MG Oral Tablet

arm B2- Dapagliflozin daily administration

ACTIVE COMPARATOR

Participants who will take a daily dose of Dapagliflozin 10 mg before and after the exercise challenge.

Drug: Dapagliflozin 10 MG Oral Tablet

Interventions

Dapagliflozin 10 MG Oral Tablet DRUG

taken once a day

Also known as: forxiga

arm B1- Dapagliflozin once only dose; arm B2- Dapagliflozin daily administration

Eligibility Criteria

• Age: 18 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-74
• T1DM diagnosed at least 12 months prior to screening test
• On insulin pump or multiple daily injections
• HbA1c \<10% (86 mmol/L)
• Engage in some form of regular exercise
• Have experienced at least one episode of exercise-induced hypoglycaemia
• Adequate treatment of celiac disease if it exists.
• Willing and able to give informed consent for participation in the trial
• In the Investigator's opinion is able and willing to comply with all trial requirements
• Will allow their General Practitioner to be notified of participation in the trial.

You may not qualify if:

• History of seizures or coma associated with hypoglycaemia in the past 2 years.
• Active diabetic retinopathy ( including proliferative diabetic retinopathy or vitreous haemorrhage in the past 6 months).
• Pregnant, breastfeeding, planning to become pregnant or not using adequate contraception methods (females only) during the course of the study
• History of ischemic heart disease ( unless has had successful reperfusion), stroke/TIA, ventricular rhythm disturbances or thromboembolic disease.
• A history of hypotension if currently on antihypertensive therapy
• An episode of diabetic ketoacidosis in the previous 1 month
• Currently on loop diuretics
• On beta-blocker medication
• A history of heart failure (NYHA Class 3 or 4)
• A history of rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption
• Renal impairment ( eGFR\<60 ml/min/1.73m2)
• Untreated Graves disease
• ECG or stress test findings indicating active ischemia or a condition that would compromise the participant's safety
• Major psychiatric disease including diagnosed eating disorders, history of drug or alcohol abuse.
• Known or suspected allergy to trial medication

Sponsors & Collaborators

• University of Oxford: lead
• The Leona M. and Harry B. Helmsley Charitable Trust: collaborator
• Oxford Brookes University: collaborator

Study Sites (1)

Clinical Research Unit, OCDEM, Churchill Hospital

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetes Mellitus; Motor Activity; Hypoglycemia

Interventions

dapagliflozin

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Behavior

Study Officials

• Ioannis Spiliotis, MD

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 25, 2018
• First Posted: May 25, 2018
• Study Start: June 2, 2018
• Primary Completion: July 14, 2021
• Study Completion: July 14, 2021
• Last Updated: May 18, 2022

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share

Locations

GB (1)