Diabetes MellitusPhase 4DAPA-Shuttle1NCT04080518
Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment
A Phase 4 study testing Dapagliflozin 10 MG [Forxiga] in people with Diabetes Mellitus and Heart Failure, run by National Heart Centre Singapore at 1 site in Singapore.
Trial summary
The purpose of this study is to investigate the effects of Dapagliflozin (FORXIGA) 10mg (n=20) and placebo (n=20) on the renal concentration mechanism, mobilization of Na+ from tissue stores, and mobilization of muscle glycogen and fat, in patients heart failure NYHA classes I and II,with or w/o T2DM in a 4-week… Read more about this study
- Who is it for?
- Ages 21 years and older
- Conditions the study is for
- Diabetes Mellitus, Heart Failure
- What is being tested?
- Dapagliflozin 10 MG [Forxiga]
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteSingapore
- Study dates
- 11 Nov 2019to 10 Nov 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 21 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of heart failure NYHA stage I or II - as shown by their medical records
- Stable anti-hypertensive treatment (>4 weeks)
- Male and female patients older than 21 years
- Willingness to participate and ability to provide informed consent
- Willingness to use effective birth control if of childbearing potential. Any kind of contraception method will be allowed for the period of the study
Who cannot join
- Patients with congestive heart failure NYHA stages I (LVEF >40%) without type 2 diabetes mellitus.
- Patients with congestive heart failure NYHA stages III and IV
- Prior serious hypersensitivity reaction to Dapagliflozin (Forxiga®)
- Treatment with any SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitors within 1 week prior to Visit 1 or during screening period until Visit 1
- Pregnant and breast-feeding women
- Diagnosis of type 1 diabetes mellitus
Show all 25Show fewer
- Patients with type 2 diabetes mellitus with HbA1C > 10.5% from most recent medical records or antidiabetic therapies other than metformin, sulfonylureas or gliptins at screening.
- Patients with type 2 diabetes mellitus whose antidiabetic treatment (metformin and/or sulfonylureas and/or gliptins) has been changed or unstable within 6 weeks prior to Visit 1
- . Unstable or rapidly progressing renal disease
- Chronic cystitis and recurrent urinary tract infections
- Impaired renal function with eGFR<45 ml/min/1.73m2 or proteinuria > 0.5 g/24h
- Severe hepatic impairment (Child-Pugh class C)
- Any major cardiovascular event/vascular disease within 3 months prior to enrolment, as assessed by the investigator
- Severe edema (as judged by the investigator)
- Active cancer, history of bladder cancer
- HIV infection
- Patients who have received an organ or bone marrow transplant
- Patients who have had major surgery in the past 3 months
- Patients who have severe comorbid conditions likely to compromise survival or study participation
- Patients who exhibit noticeable anxiety and/or claustrophobia or who exhibit severe vertigo when they are moved into the MRI scanner
- Patients with exclusion criteria for the MRI, such as:
- implanted devices (surgical clips, heart pacemakers or defibrillators, cochlear implants)
- iron-based tattoos
- any other pieces of metal or devices that are not MR-Safe anywhere in the body
- Unwillingness or other inability to cooperate
Trial locations and contacts
1 site in 1 country.
About this study
The purpose of this study is to investigate the effects of Dapagliflozin (FORXIGA) 10mg (n=20) and placebo (n=20) on the renal concentration mechanism, mobilization of Na+ from tissue stores, and mobilization of muscle glycogen and fat, in patients heart failure NYHA classes I and II,with or w/o T2DM in a 4-week double-blind, placebo-controlled, randomized study with 2 treatment arms.
Read the detailed description
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a new class of oral medications used for T2DM, which lower blood glucose levels by increasing renal sodium (Na+) and glucose excretion. However, their applications seem to go beyond glycemic control. Recent studies have shown that treatment with SGLT-2 inhibitors significantly improves cardiovascular outcome, with unprecedented reductions in cardiovascular mortality and heart failure hospitalizations. The underlying mechanism of this surprising effect is unclear.
Our hypothesis is that increased Na+ and glucose excretion induced by SGLT-2 inhibitors predisposes to water loss, to which the body responds by increasing urea production in an effort to prevent dehydration. Urea is accumulated in the renal medulla, where it provides the alternative osmotic driving force for water reabsorption. However, hepatic urea production is an energy-intense process, for which amino acids from skeletal muscle are the ideal fuel because they provide both the nitrogen and the energy needed for urea generation. Alanine is transported from muscle to the liver, where it serves as a substrate for new pyruvate generation, which can then be used for the urea cycle, glucose production or ketone body generation. In the same time, as increasing amounts of alanine are shuttled to the liver, muscle will deplete its glucose reservoirs and reprioritize fuel utilization in favour of fatty acids.
- Conditions
- Diabetes Mellitus, Heart Failure
- Being tested
- Dapagliflozin 10 MG [Forxiga]
- Medical subject headings
- Diabetes Mellitus, Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dapagliflozin 10 MG [Forxiga]Drug
Also called Placebo
24 Hour Urine Collection, Sodium (23Na) MRI and Magnetic Resonance (MR) spectroscopy scan, Blood collection for metabolomic and osmolyte analysis
| Study group | Role | What they receive |
|---|---|---|
| Experimental | Active comparator | Dapagliflozin, 10mg, oral dose, once every day Receives: Drug: Dapagliflozin 10 MG [Forxiga] |
| Control | Placebo comparator | Matching placebo for dapagliflozin, oral dose, once every day Receives: Drug: Dapagliflozin 10 MG [Forxiga] |
What is being measured
The primary outcome is the main question the study is designed to answer.
To demonstrate that SGLT-2 inhibition induces urea-dominated renal water conservation within the renal concentration mechanism. ( Change from baseline in urinary osmolyte concentration
Change from baseline in urinary osmolyte concentration
- Change from baseline in Na+
- Change from baseline in urea concentration
Measured: Baseline, Day 3, and Day 28.
Secondary outcomes (3)
To demonstrate that SGLT-2 inhibition increases plasma co-peptin levels in an effort to prevent dehydration
The investigators will study the changes in plasma co-peptin levels shortly after SGLT-2 inhibitor treatment initiation.
Measured: Baseline, Day 3 and Day 28
Analysis of skin and muscle Na+ content
The investigators will compare the changes in skin and muscle Na+ content shortly after SGLT-2 inhibitor treatment initiation. Tissue Na+ content will be measured non-invasively with 23NaMRI, using a Siemens 3T MRI scanner system.
Measured: Baseline, Day 3, and Day 28.
Analysis of glycogen and fat content in skeletal muscle and liver
The investigators will compare changes from baseline in muscle and liver lipid content (measured with 1HMRS) and assess glycogen content by metabolomic analysis in patients treated with dapagliflozin versus those receiving placebo
Measured: Baseline, Day 3 and Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Sep 2019
- Study start11 Nov 2019
- Primary completion10 Nov 2021
- Study completion10 Nov 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 Diabetes MellitusStudies 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
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This study will be a 4-week double blind, placebo-controlled, randomized study with 2 treatment arms.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Heart Centre Singapore
- Sponsor type
- University, hospital or other
- Collaborators
- Duke-NUS Graduate Medical School
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04080518
- Sponsor's protocol ID
- 2018/2414
- Acronym
- DAPA-Shuttle1
- Status last verified
- Apr 2023
- First submitted
- 26 Aug 2019
- Last updated
- 13 Apr 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Marton A, Saffari SE, Rauh M, Sun RN, Nagel AM, Linz P, Lim TT, Takase-Minegishi K, Pajarillaga A, Saw S, Morisawa N, Yam WK, Minegishi S, Totman JJ, Teo S, Teo LLY, Ng CT, Kitada K, Wild J, Kovalik JP, Luft FC, Greasley PJ, Chin CWL, Sim DKL, Titze J. Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure. J Am Coll Cardiol. 2024 Apr 16;83(15):1386-1398. doi: 10.1016/j.jacc.2024.02.020.
PubMed 38599715
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment
- ClinicalTrials.gov ID
- NCT04080518
- Acronym / sponsor ID
- DAPA-Shuttle1 / 2018/2414
- Conditions
- Diabetes Mellitus, Heart Failure
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- National Heart Centre SingaporeUniversity, hospital or other
- Collaborators
- Duke-NUS Graduate Medical School
- Study start
- 11 Nov 2019 (actual)
- Primary completion
- 10 Nov 2021 (actual)
- Study completion
- 10 Nov 2021 (actual)
- First posted
- 6 Sep 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.
The purpose of this study is to investigate the effects of Dapagliflozin (FORXIGA) 10mg (n=20) and placebo (n=20) on the renal concentration mechanism, mobilization of Na+ from tissue stores, and mobilization of muscle glycogen and fat, in patients heart failure NYHA classes I and II,with or w/o T2DM in a 4-week double-blind, placebo-controlled, randomized study with 2 treatment arms.
Detailed description
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a new class of oral medications used for T2DM, which lower blood glucose levels by increasing renal sodium (Na+) and glucose excretion. However, their applications seem to go beyond glycemic control. Recent studies have shown that treatment with SGLT-2 inhibitors significantly improves cardiovascular outcome, with unprecedented reductions in cardiovascular mortality and heart failure hospitalizations. The underlying mechanism of this surprising effect is unclear.
Our hypothesis is that increased Na+ and glucose excretion induced by SGLT-2 inhibitors predisposes to water loss, to which the body responds by increasing urea production in an effort to prevent dehydration. Urea is accumulated in the renal medulla, where it provides the alternative osmotic driving force for water reabsorption. However, hepatic urea production is an energy-intense process, for which amino acids from skeletal muscle are the ideal fuel because they provide both the nitrogen and the energy needed for urea generation. Alanine is transported from muscle to the liver, where it serves as a substrate for new pyruvate generation, which can then be used for the urea cycle, glucose production or ketone body generation. In the same time, as increasing amounts of alanine are shuttled to the liver, muscle will deplete its glucose reservoirs and reprioritize fuel utilization in favour of fatty acids.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- This study will be a 4-week double blind, placebo-controlled, randomized study with 2 treatment arms.
| Arm | Type | Receives |
|---|---|---|
| Experimental | Active comparator | Drug: Dapagliflozin 10 MG [Forxiga]Dapagliflozin, 10mg, oral dose, once every day |
| Control | Placebo comparator | Drug: Dapagliflozin 10 MG [Forxiga]Matching placebo for dapagliflozin, oral dose, once every day |
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Diagnosis of heart failure NYHA stage I or II - as shown by their medical records
- Stable anti-hypertensive treatment (>4 weeks)
- Male and female patients older than 21 years
- Willingness to participate and ability to provide informed consent
- Willingness to use effective birth control if of childbearing potential. Any kind of contraception method will be allowed for the period of the study
Key exclusion criteria (25 listed)
- Patients with congestive heart failure NYHA stages I (LVEF >40%) without type 2 diabetes mellitus.
- Patients with congestive heart failure NYHA stages III and IV
- Prior serious hypersensitivity reaction to Dapagliflozin (Forxiga®)
- Treatment with any SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitors within 1 week prior to Visit 1 or during screening period until Visit 1
- Pregnant and breast-feeding 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 |
|---|---|---|
| Dapagliflozin 10 MG [Forxiga]Also: Placebo24 Hour Urine Collection, Sodium (23Na) MRI and Magnetic Resonance (MR) spectroscopy scan, Blood collection for metabolomic and osmolyte analysis | Drug | Control, Experimental |
Primary outcome
To demonstrate that SGLT-2 inhibition induces urea-dominated renal water conservation within the renal concentration mechanism. ( Change from baseline in urinary osmolyte concentration
Time frame: Baseline, Day 3, and Day 28.
Change from baseline in urinary osmolyte concentration 1. Change from baseline in Na+ 2. Change from baseline in urea concentration
3 secondary outcomes
To demonstrate that SGLT-2 inhibition increases plasma co-peptin levels in an effort to prevent dehydration
Time frame: Baseline, Day 3 and Day 28
Analysis of skin and muscle Na+ content
Time frame: Baseline, Day 3, and Day 28.
Analysis of glycogen and fat content in skeletal muscle and liver
Time frame: Baseline, Day 3 and Day 28
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 13 Apr 2023.
- Derived from this study: PubMed 38599715Marton A, Saffari SE, Rauh M, Sun RN, Nagel AM, Linz P, Lim TT, Takase-Minegishi K, Pajarillaga A, Saw S, Morisawa N, Yam WK, Minegishi S, Totman JJ, Teo S, Teo LLY, Ng CT, Kitada K, Wild J, Kovalik JP, Luft FC, Greasley PJ, Chin CWL, Sim DKL, Titze J. Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure. J Am Coll Cardiol. 2024 Apr 16;83(15):1386-1398. doi: 10.1016/j.jacc.2024.02.020.
- 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 Dapagliflozin 10 MG [Forxiga] in people with Diabetes Mellitus and Heart Failure, run by National Heart Centre Singapore at 1 site in Singapore.
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 5 inclusion and 25 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 13 Apr 2023. 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 Singapore. 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?
To demonstrate that SGLT-2 inhibition induces urea-dominated renal water conservation within the renal concentration mechanism. ( Change from baseline in urinary osmolyte concentration (time frame: Baseline, Day 3, and Day 28.). 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 NCT04080518, 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 13 Apr 2023.