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

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ClinicalTrials.gov Identifier: NCT04193566
Recruitment Status : Not yet recruiting
First Posted : December 10, 2019
Last Update Posted : December 10, 2019
Sponsor:
Collaborators:
Glostrup University Hospital, Copenhagen
Novo Nordisk A/S
Information provided by (Responsible Party):
Steno Diabetes Center Copenhagen

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.


Condition or disease Intervention/treatment Phase
Nephropathy Hypoxia Mitochondrial Alteration Type 1 Diabetes Autonomic Neuropathy, Diabetic Drug: Forxiga Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Randomized, double blinded, placebo-controlled, cross-over intervention study
Masking: Double (Participant, Investigator)
Masking Description: Group allocation is concealed to patients as well as investigators. 60 sequentially numbered, opaque, sealed envelopes will be produced by Glostrup Apotek. All persons involved in the conduct of the study are blinded to the randomization code. Randomization codes and envelopes are stored securely at the study site available only for the unblinded site staff in charge of randomizing subjects and dispensing study products to subjects. Sealed codes are marked according to randomization code and distributed according to a pre-distributed order. Should unblinding of a study participant be necessary because of an emergency, a dedicated person at Steno Diabetes Center Copenhagen, not involved in the study, will perform the procedure. Alternatively, the Principal investigator will be able to perform unblinding
Primary Purpose: Treatment
Official Title: Acute Effects of Sodium-glucose Cotransporter-2 Inhibition on Renal Oxygenation and Autonomic Function in Type 1 Diabetes
Estimated Study Start Date : February 1, 2020
Estimated Primary Completion Date : February 1, 2021
Estimated Study Completion Date : March 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arm Intervention/treatment
Active Comparator: 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.

Drug: 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.

Other Name: dapagliflozin

Placebo Comparator: 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.

Drug: 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.

Other Name: dapagliflozin




Primary Outcome Measures :
  1. Change in Renal oxygenation [ Time Frame: From baseline to +3 hours from intervention ]
    Blood Oxygen Level Dependent (BOLD) Magnetic Resonance Imaging (MRI) assessing the transverse relaxation time of atomic nuclei in the tissue (T2*) in miliseconds (ms).

  2. Change in Renal oxygenation [ Time Frame: From baseline to +6 hours from intervention ]
    BOLD MRI assessing the transverse relaxation time of atomic nuclei in the tissue (T2*) in miliseconds (ms).


Secondary Outcome Measures :
  1. Change in renal cortical and medullary perfusion [ Time Frame: From baseline to +3 hours from intervention ]
    Renal tissue perfusion can be measured noninvasively with MRI using arterial spin labelling (ASL). It is measured in mL/g/min.

  2. Change in renal cortical and medullary perfusion [ Time Frame: From baseline to +6 hours from intervention ]
    Renal tissue perfusion can be measured with MRI using arterial spin labelling (ASL). It is measured in mL/g/min.

  3. Change in renal artery flow [ Time Frame: From baseline to +3 hours from intervention ]
    Renal artery flow can be measured by using phase contrast (PC) MRI. It is measured in mL/min.

  4. Change in renal artery flow [ Time Frame: From baseline to +6 hours from intervention ]
    Renal artery flow can be measured by using phase contrast (PC) MRI. It is measured in mL/min.

  5. Change in renal oxygen consumption [ Time Frame: From baseline to +3 hours from intervention ]
    Renal oxygen consumption can be measured using Q-flow combined with BOLD MRI. It is measured in pmol/min/microgram protein.

  6. Change in renal oxygen consumption [ Time Frame: From baseline to +6 hours from intervention ]
    Renal oxygen consumption can be measured using Q-flow combined with BOLD MRI. pmol/min/microgram protein

  7. Change in peripheral capillary oxygen saturation (SpO2) [ Time Frame: From baseline to +3 hours from intervention ]
    Pulse oximetry on index finger of the right hand. Estimates blood oxygen saturation from capillary blood. Measured in %.

  8. Change in peripheral capillary oxygen saturation (SpO2) [ Time Frame: From baseline to +6 hours from intervention ]
    Pulse oximetry on index finger of the right hand. Estimates blood oxygen saturation from capillary blood. Measured in %.

  9. Change in blood oxygen partial pressure (PaO2) [ Time Frame: From baseline to +3 hours from intervention ]
    Blood gas analysis on arterial blood. Measured in kPa.

  10. Change in blood oxygen partial pressure (PaO2) [ Time Frame: From baseline to +6 hours from intervention ]
    Blood gas analysis on arterial blood. Measured in kPa.

  11. Change in arterial blood oxygen saturation [ Time Frame: From baseline to +3 hours from intervention ]
    Blood gas analysis on arterial blood. Measured in %.

  12. Change in arterial blood oxygen saturation [ Time Frame: From baseline to +6 hours from intervention ]
    Blood gas analysis on arterial blood. Measured in %.

  13. Change in Peripheral Blood Monocyte mitochondrial function [ Time Frame: From baseline to +12 hours from intervention ]
    Seahorse X96 analyzer. Analyzes the oxygen consumption rate (OCR), measured in pMoles/min.

  14. Change in levels of circulating inflammatory markers [ Time Frame: From baseline to +12 hours from intervention ]
    Commercially available panel from the company Olink. Includes 92 biomarkers. Information on the panel can be found here: https://www.olink.com/products/inflammation/#.

  15. Change in baroreflex sensitivity [ Time Frame: From baseline to +12 hours from intervention ]
    Calculated from continous blood pressure and the distance between the R-waves in a continuous ecg. Baroreflex sensitivity describes how much heart-rate changes when blood pressure changes. Assessment of baroreflex sensitivity is done in a measurement of 5 minutes. The unit is ms/mmHg.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria healthy controls:

  • 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

Inclusion criteria persons with type 1 diabetes:

  • 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 for all:

  • 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
  • Exclusion criteria for MRI

    • 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)
  • Exclusion criteria for arterial blood gas sampling (only patients with type 1 diabetes)

    • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04193566


Contacts
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Contact: Jens Christian Laursen, MD 004531913252 jens.christian.laursen.01@regionh.dk

Sponsors and Collaborators
Steno Diabetes Center Copenhagen
Glostrup University Hospital, Copenhagen
Novo Nordisk A/S

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Responsible Party: Steno Diabetes Center Copenhagen
ClinicalTrials.gov Identifier: NCT04193566    
Other Study ID Numbers: H-19052662
2019-004557-92 ( EudraCT Number )
First Posted: December 10, 2019    Key Record Dates
Last Update Posted: December 10, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Diabetic Neuropathies
Diabetes Mellitus
Diabetes Mellitus, Type 1
Hypoxia
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Diabetes Complications
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs