Acute Effects of SGLT2 Inhibition on Renal Oxygenation and Autonomic Function in Type 1 Diabetes

NCT ID: NCT04193566

Last Updated: 2021-02-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-01
• Study Completion Date: 2021-01-01

Brief Summary

Background: Inhibiting the sodium-glucose cotransporter-2 (SGLT2) has been observed to reduce risk of cardiovascular events and kidney failure in type 2 diabetes. The exact mechanisms of the beneficial effects of SGLT2 inhibition (SGLT2i) are still unknown. Kidney hypoxia has been demonstrated in diabetic kidney disease and SGLT2i is thought to relieve hypoxia in the kidneys. Mitochondrial dysfunction and autonomic dysfunction might also contribute to kidney hypoxia.

Objective: The primary aim of the study is to assess the acute effects of SGLT2 inhibition on parameters reflecting oxygenation and oxygen consumption of the human kidney in persons with type 1 diabetes. Exploratory aims are to investigate acute changes in oxygen availability and oxygen access to the kidneys after SGLT2i. This include measures of peripheral blood oxygenation, mitochondrial function and autonomic function.

Methods: Acute intervention study with oral dapagliflozin given in two doses each of 50 mg or matching placebo as intervention. Kidney oxygenation and perfusion parameters will be assessed by blood-oxygen-dependant level magnetic resonance imaging. Mitochondrial function will be assessed by extracellular flux analysis on lymphocytes. Autonomic function will be assessed by measuring baroreflex sensitivity.

Design: Randomized, double blinded, placebo-controlled, cross-over intervention study.

Study population: Fifteen healthy controls are recruited by advertisement and 15 patients with type 1 diabetes recruited from Steno Diabetes Center Copenhagen.

Endpoints: Primary end-point: Renal cortical and medullary oxygenation (T2*). Exploratory end-points: Renal cortical and medullary perfusion, renal artery flow, renal oxygen consumption, peripheral capillary oxygen saturation (SpO2), arterial oxygen partial pressure (PaO2), arterial oxygen saturation (SaO2), lymphocyte mitochondrial function, baroreflex sensitivity.

Timeframe: Inclusion of patients from January 2020. Last patient last visit January 2021. Data analysis completed spring 2021, presentation autumn 2021 and publications Winter 2021.

Conditions

Nephropathy; Hypoxia; Mitochondrial Alteration; Type 1 Diabetes; Autonomic Neuropathy, Diabetic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Dapagliflozin

Patients in the active arm will be treated with dapagliflozin 50 mg once on site for visit 2 and once at home on the evening before visit 3.

Forxiga®, dapagliflozin 10 mg film-coated tablet.

For further information please refer to:

https://www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf.

Group Type: ACTIVE_COMPARATOR

Forxiga

Intervention Type: DRUG

Forxiga®, dapagliflozin 10 mg film-coated tablet.

For further information please refer to:

https://www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf.

Common side effects include hypoglycemia, hypotension, elevated hematocrite, dyslipidemia, back pain, dizziness, skin rash, urinary tract infection, vulvovaginitis and dehydration. Very rare incidents of ketoacidosis have been observed. Side effects have only been observed after use in longer periods and not in single-dose usage, as planned in the present study. A dose of 50 mg has been chosen to achieve optimal efficacy. Once-per-day doses of dapagliflozin for 12 weeks of 2.5 mg, 5 mg, 10 mg, 20 mg and 50 mg have been demonstrated to be relatively safe across the mentioned doses (20) and no apparent risk is expected from instituting two single-doses of 50 mg dapagliflozin.

Placebo

Patients in the placebo arm will be treated with placebo once on site for visit 2 and once at home on the evening before visit 3.

Placebo drug:

The composition equals the composition of Forxiga® - just with the active ingredient omitted. Active drug and placebo are similar in appearance and smell.

Group Type: PLACEBO_COMPARATOR

Forxiga

Intervention Type: DRUG

Forxiga®, dapagliflozin 10 mg film-coated tablet.

For further information please refer to:

https://www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf.

Common side effects include hypoglycemia, hypotension, elevated hematocrite, dyslipidemia, back pain, dizziness, skin rash, urinary tract infection, vulvovaginitis and dehydration. Very rare incidents of ketoacidosis have been observed. Side effects have only been observed after use in longer periods and not in single-dose usage, as planned in the present study. A dose of 50 mg has been chosen to achieve optimal efficacy. Once-per-day doses of dapagliflozin for 12 weeks of 2.5 mg, 5 mg, 10 mg, 20 mg and 50 mg have been demonstrated to be relatively safe across the mentioned doses (20) and no apparent risk is expected from instituting two single-doses of 50 mg dapagliflozin.

Interventions

Forxiga

Forxiga®, dapagliflozin 10 mg film-coated tablet.

For further information please refer to:

https://www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf.

Common side effects include hypoglycemia, hypotension, elevated hematocrite, dyslipidemia, back pain, dizziness, skin rash, urinary tract infection, vulvovaginitis and dehydration. Very rare incidents of ketoacidosis have been observed. Side effects have only been observed after use in longer periods and not in single-dose usage, as planned in the present study. A dose of 50 mg has been chosen to achieve optimal efficacy. Once-per-day doses of dapagliflozin for 12 weeks of 2.5 mg, 5 mg, 10 mg, 20 mg and 50 mg have been demonstrated to be relatively safe across the mentioned doses (20) and no apparent risk is expected from instituting two single-doses of 50 mg dapagliflozin.

Intervention Type: DRUG

Other Intervention Names

dapagliflozin

Eligibility Criteria

Inclusion Criteria

• Written informed consent must be provided before participation
• Male or female patients > 18 years of age
• Capable of lying in a MR-scanner for two hours

• Written informed consent must be provided before participation
• Male or female patients >18 years of age with a diagnosis of type 1 diabetes (WHO criteria)
• Urinary albumin creatinine ratio (UACR) ≥30 mg/g in 2 out of 3 consecutive samples (albuminuria) prior to randomization assessed from electronic laboratory database.
• Capable of lying in a MR-scanner for two hours

Exclusion Criteria

• Non-diabetic kidney disease as indicated by medical history and/or laboratory findings
• Renal failure (eGFR<15 ml/min/1.73m2), dialysis or kidney transplantation
• Treatment with beta-blocking medication
• Uncontrolled arrhythmia, 2. or 3. degree AV-block or sick sinus syndrome - assessed from a standard 12-lead electrocardiogram
• Pregnancy or breastfeeding (urine HCG is performed on all fertile women)
• Systolic blood pressure < 90 or > 200 mmHg
• Patients who, in the judgement of the investigator, is incapable of participating

• Claustrophobia
• Known heart disease
• Known lung disease
• Have had surgery the past six weeks
• Have foreign bodies of metal in the body (e.g. pacemaker, metal plates, metal screws)

• Absent pulse
• Raynauds syndrome
• Buergers Disease (thromboangiitis obliterans)
• Inadequate or interrupted circulation
• Anticoagulation treatment
• Coagulopathies (hypo or hyper coagulable states)
• Arterial atherosclerosis
• Insufficient collateral perfusion
• Partial or full thickness burns over the cannulation site
• Synthetic arterial or vascular grafts or infection at the proposed site of cannulation Patients with type 1 diabetes will have the possibility to participate in the study without getting arterial blood gas sampling.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Glostrup University Hospital, Copenhagen

OTHER

Sponsor Role: collaborator

Novo Nordisk A/S

INDUSTRY

Sponsor Role: collaborator

Steno Diabetes Center Copenhagen

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Steno Diabetes Center Copenhagen

Gentofte Municipality, , Denmark

Countries

Denmark

References

Laursen JC, Sondergaard-Heinrich N, de Melo JML, Haddock B, Rasmussen IKB, Safavimanesh F, Hansen CS, Storling J, Larsson HBW, Groop PH, Frimodt-Moller M, Andersen UB, Rossing P. Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial. EClinicalMedicine. 2021 Jun 28;37:100895. doi: 10.1016/j.eclinm.2021.100895. eCollection 2021 Jul.

Reference Type: DERIVED

PMID: 34386735 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2019-004557-92

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

H-19052662

Identifier Type: -

Identifier Source: org_study_id