NephropathyPhase 4AstronautNCT04193566
Acute Effects of SGLT2 Inhibition on Renal Oxygenation and Autonomic Function in Type 1 Diabetes
A Phase 4 study testing Forxiga in people with Nephropathy and Hypoxia, run by Steno Diabetes Center Copenhagen at 1 site in Denmark.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Nephropathy, Hypoxia, Mitochondrial Alteration
- What is being tested?
- Forxiga
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteDenmark
- Study dates
- 1 Feb 2020to 1 Jan 2021
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 23Show fewer
- 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)
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Acute Effects of Sodium-glucose Cotransporter-2 Inhibition on Renal Oxygenation and Autonomic Function in Type 1 Diabetes
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.
Read more
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
- Being tested
- Forxiga
- Medical subject headings
- Kidney Diseases, Hypoxia, Diabetes Mellitus, Type 1, Diabetic Neuropathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ForxigaDrug
Also called dapagliflozin
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.
| Study group | Role | What they receive |
|---|---|---|
| Dapagliflozin | Active comparator | 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. Receives: Drug: Forxiga |
| Placebo | Placebo comparator | 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. Receives: Drug: Forxiga |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Renal oxygenation
Blood Oxygen Level Dependent (BOLD) Magnetic Resonance Imaging (MRI) assessing the transverse relaxation time of atomic nuclei in the tissue (T2*) in miliseconds (ms).
Measured: From baseline to +3 hours from intervention
Change in Renal oxygenation
BOLD MRI assessing the transverse relaxation time of atomic nuclei in the tissue (T2*) in miliseconds (ms).
Measured: From baseline to +6 hours from intervention
Secondary outcomes (15)
Change in renal cortical and medullary perfusion
Renal tissue perfusion can be measured noninvasively with MRI using arterial spin labelling (ASL). It is measured in mL/g/min.
Measured: From baseline to +3 hours from intervention
Change in renal cortical and medullary perfusion
Renal tissue perfusion can be measured with MRI using arterial spin labelling (ASL). It is measured in mL/g/min.
Measured: From baseline to +6 hours from intervention
Change in renal artery flow
Renal artery flow can be measured by using phase contrast (PC) MRI. It is measured in mL/min.
Measured: From baseline to +3 hours from intervention
Change in renal artery flow
Renal artery flow can be measured by using phase contrast (PC) MRI. It is measured in mL/min.
Measured: From baseline to +6 hours from intervention
Change in renal oxygen consumption
Renal oxygen consumption can be measured using Q-flow combined with BOLD MRI. It is measured in pmol/min/microgram protein.
Measured: From baseline to +3 hours from intervention
Change in renal oxygen consumption
Renal oxygen consumption can be measured using Q-flow combined with BOLD MRI. pmol/min/microgram protein
Measured: From baseline to +6 hours from intervention
Change in peripheral capillary oxygen saturation (SpO2)
Pulse oximetry on index finger of the right hand. Estimates blood oxygen saturation from capillary blood. Measured in %.
Measured: From baseline to +3 hours from intervention
Change in peripheral capillary oxygen saturation (SpO2)
Pulse oximetry on index finger of the right hand. Estimates blood oxygen saturation from capillary blood. Measured in %.
Measured: From baseline to +6 hours from intervention
Change in blood oxygen partial pressure (PaO2)
Blood gas analysis on arterial blood. Measured in kPa.
Measured: From baseline to +3 hours from intervention
Change in blood oxygen partial pressure (PaO2)
Blood gas analysis on arterial blood. Measured in kPa.
Measured: From baseline to +6 hours from intervention
Change in arterial blood oxygen saturation
Blood gas analysis on arterial blood. Measured in %.
Measured: From baseline to +3 hours from intervention
Change in arterial blood oxygen saturation
Blood gas analysis on arterial blood. Measured in %.
Measured: From baseline to +6 hours from intervention
Change in Peripheral Blood Monocyte mitochondrial function
Seahorse X96 analyzer. Analyzes the oxygen consumption rate (OCR), measured in pMoles/min.
Measured: From baseline to +12 hours from intervention
Change in levels of circulating inflammatory markers
Commercially available panel from the company Olink. Includes 92 biomarkers. Information on the panel can be found here: https://www.olink.com/products/inflammation/#.
Measured: From baseline to +12 hours from intervention
Change in baroreflex sensitivity
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.
Measured: From baseline to +12 hours from intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Dec 2019
- Study start1 Feb 2020
- Primary completion1 Sep 2020
- Study completion1 Jan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for NephropathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Randomized, double blinded, placebo-controlled, cross-over intervention study
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Steno Diabetes Center Copenhagen
- Sponsor type
- University, hospital or other
- Collaborators
- Glostrup University Hospital, Copenhagen, Novo Nordisk A/S
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04193566
- Sponsor's protocol ID
- H-19052662
- Other IDs
- 2019-004557-92, 2019
- Acronym
- Astronaut
- Status last verified
- Jan 2021
- First submitted
- 3 Dec 2019
- Last updated
- 3 Feb 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 34386735
Study at a glance
From the registry record, last updated by the sponsor on 3 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Acute Effects of Sodium-glucose Cotransporter-2 Inhibition on Renal Oxygenation and Autonomic Function in Type 1 Diabetes
- ClinicalTrials.gov ID
- NCT04193566
- Acronym / sponsor ID
- Astronaut / H-19052662
- Conditions
- Nephropathy, Hypoxia, Mitochondrial Alteration, Type 1 Diabetes, Autonomic Neuropathy, Diabetic
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Steno Diabetes Center CopenhagenUniversity, hospital or other
- Collaborators
- Glostrup University Hospital, Copenhagen, Novo Nordisk A/S
- Study start
- 1 Feb 2020 (actual)
- Primary completion
- 1 Sep 2020 (actual)
- Study completion
- 1 Jan 2021 (actual)
- First posted
- 10 Dec 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- Randomized, double blinded, placebo-controlled, cross-over intervention study
| Arm | Type | Receives |
|---|---|---|
| Dapagliflozin | Active comparator | Drug: ForxigaPatients 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. |
| Placebo | Placebo comparator | Drug: ForxigaPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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)
Key exclusion criteria (23 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ForxigaAlso: dapagliflozinForxiga®, 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. | Drug | Dapagliflozin, Placebo |
Primary outcome
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).
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).
15 secondary outcomes
Change in renal cortical and medullary perfusion
Time frame: From baseline to +3 hours from intervention
Change in renal cortical and medullary perfusion
Time frame: From baseline to +6 hours from intervention
Change in renal artery flow
Time frame: From baseline to +3 hours from intervention
Change in renal artery flow
Time frame: From baseline to +6 hours from intervention
Change in renal oxygen consumption
Time frame: From baseline to +3 hours from intervention
Change in renal oxygen consumption
Time frame: From baseline to +6 hours from intervention
Change in peripheral capillary oxygen saturation (SpO2)
Time frame: From baseline to +3 hours from intervention
Change in peripheral capillary oxygen saturation (SpO2)
Time frame: From baseline to +6 hours from intervention
Change in blood oxygen partial pressure (PaO2)
Time frame: From baseline to +3 hours from intervention
Change in blood oxygen partial pressure (PaO2)
Time frame: From baseline to +6 hours from intervention
Change in arterial blood oxygen saturation
Time frame: From baseline to +3 hours from intervention
Change in arterial blood oxygen saturation
Time frame: From baseline to +6 hours from intervention
Change in Peripheral Blood Monocyte mitochondrial function
Time frame: From baseline to +12 hours from intervention
Change in levels of circulating inflammatory markers
Time frame: From baseline to +12 hours from intervention
Change in baroreflex sensitivity
Time frame: From baseline to +12 hours from intervention
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Feb 2021.
- Derived from this study: PubMed 34386735Laursen 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Forxiga in people with Nephropathy and Hypoxia, run by Steno Diabetes Center Copenhagen at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Renal oxygenation (time frame: From baseline to +3 hours from intervention). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04193566, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Feb 2021.