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Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment (DAPA-Shuttle1)

Primary Purpose

Diabetes Mellitus, Heart Failure

Status

Completed

Phase

Phase 4

Locations

Singapore

Study Type

Interventional

Intervention

Dapagliflozin 10 MG [Forxiga]

About this trial

This is an interventional basic science trial for Diabetes Mellitus

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

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
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:
1. implanted devices (surgical clips, heart pacemakers or defibrillators, cochlear implants)
2. iron-based tattoos
3. any other pieces of metal or devices that are not MR-Safe anywhere in the body
Unwillingness or other inability to cooperate

Sites / Locations

National Heart Centre Singapore

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Experimental

Control

Arm Description

Dapagliflozin, 10mg, oral dose, once every day

Matching placebo for dapagliflozin, oral dose, once every day

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

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.

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

Full Information

NCT ID

NCT04080518

First Posted

August 26, 2019

Last Updated

April 11, 2023

Sponsor

National Heart Centre Singapore

Collaborators

Duke-NUS Medical School (Singapore)

1. Study Identification

Unique Protocol Identification Number

NCT04080518

Brief Title

Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment

Acronym

DAPA-Shuttle1

Official Title

Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Completed

Study Start Date

November 11, 2019 (Actual)

Primary Completion Date

November 10, 2021 (Actual)

Study Completion Date

November 10, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Heart Centre Singapore

Collaborators

Duke-NUS Medical School (Singapore)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief 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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus, Heart Failure

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

This study will be a 4-week double blind, placebo-controlled, randomized study with 2 treatment arms.

Masking

ParticipantCare ProviderInvestigator

Masking Description

The assignment of consented patients will occur in a blinded fashion using a randomization scheme generated by a statistician who is not part of the study team and has no contact with the study subject. Once eligibility criteria are met, study participants will be randomly assigned to receive either Dapagliflozin 10mg or matching, identically appearing placebo. Stratified random sampling (by gender) will be performed in order to minimize selection bias. Access to the randomisation code will be controlled and documented. Relevant parties will be blinded to the treatment group assignment.

Allocation

Randomized

Enrollment

40 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Experimental

Arm Type

Active Comparator

Arm Description

Dapagliflozin, 10mg, oral dose, once every day

Arm Title

Control

Arm Type

Placebo Comparator

Arm Description

Matching placebo for dapagliflozin, oral dose, once every day

Intervention Type

Drug

Intervention Name(s)

Dapagliflozin 10 MG [Forxiga]

Other Intervention Name(s)

Placebo

Intervention Description

24 Hour Urine Collection, Sodium (23Na) MRI and Magnetic Resonance (MR) spectroscopy scan, Blood collection for metabolomic and osmolyte analysis

Primary Outcome Measure Information:

Title

To demonstrate that SGLT-2 inhibition induces urea-dominated renal water conservation within the renal concentration mechanism. ( Change from baseline in urinary osmolyte concentration

Description

Change from baseline in urinary osmolyte concentration Change from baseline in Na+ Change from baseline in urea concentration

Time Frame

Baseline, Day 3, and Day 28.

Secondary Outcome Measure Information:

Title

To demonstrate that SGLT-2 inhibition increases plasma co-peptin levels in an effort to prevent dehydration

Description

The investigators will study the changes in plasma co-peptin levels shortly after SGLT-2 inhibitor treatment initiation.

Time Frame

Baseline, Day 3 and Day 28

Title

Analysis of skin and muscle Na+ content

Description

Time Frame

Baseline, Day 3, and Day 28.

Title

Analysis of glycogen and fat content in skeletal muscle and liver

Description

Time Frame

Baseline, Day 3 and Day 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Exclusion Criteria: 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 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

Facility Information:

Facility Name

National Heart Centre Singapore

City

Singapore

ZIP/Postal Code

169609

Country

Singapore

12. IPD Sharing Statement

Plan to Share IPD

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Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment

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