Acute Heart FailurePhase 3DRAIN-AHFNCT06166654
Optimal Diuretic Therapies for Acute Heart Failure With Volume Overload
A Phase 3 study testing Acetazolamide and Metolazone 2.5 MG in people with Acute Heart Failure, run by Johannes Grand at 6 sites in Denmark.
Trial summary
This trial aims to identify the best strategy for treating acute heart failure (AHF) with volume overload in patients at risk of diuretic resistance. It is a double-blinded, randomized, controlled, multicenter study comparing loop-diuretics combined with metolazone, loop-diuretics combined with acetazolamide, and… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Heart Failure
- What is being tested?
- Acetazolamide and Metolazone 2.5 MG
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 939 participants
- Where
- 6 sitesDenmark
- Study dates
- 5 Sep 2024to 1 May 2028
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
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
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years
- Acute hospital admission with a clinical diagnosis of acute heart failure with volume overload.
- Display risk of diuretic resistance, characterized by:
- Daily loop-diuretics administration for a minimum of 7 days before admission, or
- Insufficient decongestion observed in the preceding 24 hours (weight reduction <500g or negative fluid balance <1L) despite being treated with high-dose IV loop diuretic (equivalent to ≥120 mg IV furosemide within 24 hours).
- Clinical signs of congestion, indicated by one or more of the following: pitting peripheral edema, ascites, elevated jugular venous pressure, or radiological/ultrasonic evidence of pulmonary congestion.
Who cannot join
- Acute coronary syndrome
- Systolic blood pressure <85 mmHg
- Use of renal replacement therapy or ultrafiltration in-hospital before study inclusion
- Treatment with acetazolamide or metolazone during the index hospitalization prior to randomization
- Known allergy to any of the used drugs
- Severe hypokalemia (<2.5 mmol/l) or severe hyponatremia (<125 mmol/l)
- Severe hepatic impairment defined as an INR >1.5 (not due to anticoagulant therapy) and/or a Child-Pugh score ≥B7
- Known pregnancy
Trial locations and contacts
6 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Sandra Tonning, MD contact
6 sites in 1 country
Denmark6 sites, 6 recruiting
- Recruiting
Aarhus University Hospital
Aarhus N, 8200
Henrik Vase, 35454360, henrvase@rm.dk
Henrik Vase
- Recruiting
Bispebjerg Hospital
Copenhagen, 2400
Jens Jakob Thune, MD, PhD, +4538683767, jens.jakob.thune@regionh.dk
Jens Jakob Thune, MD, PhD
- Recruiting
Herlev Hospital
Herlev, 2730
Morten Schou, MD, PhD, morten.schou.04@regionh.dk
Morten Schou, MD, PhD
- Recruiting
Amager-Hvidovre Hospital
Hvidovre, Capital Region of Denmark, 2650
Johannes Grand, MD, PhD, MPH, +4535452121, johannes.grand@regionh.dk
Morten Petersen, MD, PhD
- Not yet recruiting
Odense University Hospital
Odense C, 5000
Premavathanan Muthukumarapillai, +4540783826, premavathanan.muthukumarapillai@rsyd.dk
Premavathanan Muthukumarapillai
- Recruiting
Zealand University Hospital
Roskilde, 4000
Martin Frydland, MD, PhD, 35454360, mafry@regionsjaelland.dk
Julie Vishram-Nielsen
About this study
Official title: Optimal Diuretic Therapies for Acute Heart Failure With Volume Overload - A Randomized Clinical Trial
This trial aims to identify the best strategy for treating acute heart failure (AHF) with volume overload in patients at risk of diuretic resistance. It is a double-blinded, randomized, controlled, multicenter study comparing loop-diuretics combined with metolazone, loop-diuretics combined with acetazolamide, and loop-diuretics with matching placebos.
Eligible participants are adults aged 18 years or older who are hospitalized with AHF and have clinical signs of congestion and a risk of diuretic resistance.
Read more
The primary outcome is the number of days alive and out of hospital through day 30. Secondary outcomes are clinical benefit at 30 days, assessed using a hierarchical win ratio; days alive and out of hospital through day 90; and the duration of the index hospital admission.
The trial aims to enroll 939 participants across three treatment arms (313 per arm). The sample size is based on detecting a clinically relevant between-group difference of two days alive and out of hospital through day 30, with 80% power and adjustment for comparisons between the three groups.
Read the detailed description
Intravenous loop diuretics remain the cornerstone of treatment for acute heart failure with volume overload. However, a substantial proportion of patients experience an insufficient diuretic response, which may contribute to persistent congestion, prolonged hospitalization, and adverse clinical outcomes. Diuretic resistance may arise from several mechanisms, including reduced delivery of diuretics to their site of action, impaired renal function, and compensatory sodium reabsorption in nephron segments not targeted by loop diuretics.
Sequential nephron blockade represents a potential strategy to overcome diuretic resistance by combining diuretics acting at different sites of the nephron. Acetazolamide inhibits carbonic anhydrase in the proximal tubule, thereby reducing proximal sodium bicarbonate reabsorption and increasing sodium delivery to downstream nephron segments. Metolazone is a thiazide-like diuretic that inhibits sodium-chloride cotransport in the distal convoluted tubule, potentially counteracting compensatory distal sodium reabsorption during loop diuretic treatment.
Although both approaches may enhance natriuresis and facilitate decongestion, they differ in their mechanisms of action, electrolyte effects, and potential adverse events. Direct randomized comparisons of these strategies in patients hospitalized with acute heart failure are limited, and uncertainty remains regarding their relative clinical effectiveness and safety.
This trial is designed to address this evidence gap by directly comparing proximal and distal tubular diuretic strategies as adjuncts to intravenous loop diuretic therapy. The findings may help establish the optimal pharmacological approach to decongestion in patients with acute heart failure who are at risk of diuretic resistance.
- Conditions
- Acute Heart Failure
- Being tested
- Acetazolamide, Metolazone 2.5 MG, Double-placebo
- Keywords
- acute heart failure, decongestion, diuretic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AcetazolamideDrug
Acetazolamide 500 mg IV at randomization (day 0) and on the next three mornings (days 1, 2 and 3), with a matching placebo-metolazone tablet at each administration. The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines.
Metolazone 2.5 MGDrug
Metolazone 2.5 mg orally at randomization (day 0) and on the next three mornings (days 1, 2 and 3), with a matching placebo-acetazolamide injection at each administration. The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines.
Double-placeboOther
Matching placebo-acetazolamide injection and placebo-metolazone tablet at randomization (day 0) and on the next three mornings (days 1, 2 and 3), in addition to usual care with loop-diuretics (SGLT2 inhibitors are allowed). The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines.
| Study group | Role | What they receive |
|---|---|---|
| Acetazolamide | Active comparator | Acetazolamide 500 mg IV at randomization (day 0) and on the next three mornings (days 1, 2 and 3), with a matching placebo-metolazone tablet at each administration. The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines. Receives: Drug: Acetazolamide |
| Metolazone | Active comparator | Metolazone 2.5 mg orally at randomization (day 0) and on the next three mornings (days 1, 2 and 3), with a matching placebo-acetazolamide injection at each administration. The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines. Receives: Drug: Metolazone 2.5 MG |
| Placebo | Placebo comparator | Matching placebo-acetazolamide injection and placebo-metolazone tablet at randomization (day 0) and on the next three mornings (days 1, 2 and 3), in addition to usual care with loop-diuretics (SGLT2 inhibitors are allowed). The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines. Receives: Other: Double-placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Days alive and out of hospital through day 30
Number of days alive and out of hospital during the 30-day period from inclusion. A return visit to the emergency department with discharge on the same day counts as one day in hospital.
Measured: 30 days
Secondary outcomes (3)
Clinical benefit at 30 days assessed using a hierarchical win ratio
Clinical benefit at 30 days, consisting of all-cause death, readmission after discharge from the index hospitalization, new receipt of renal replacement therapy, or persistent renal dysfunction (final inpatient creatinine ≥200% of baseline), assessed using a hierarchical win-ratio approach.
Measured: 30 days
Days alive and out of hospital through day 90
Number of days alive and out of hospital from inclusion through day 90.
Measured: 90 days
Duration of the index hospital admission
Number of days admitted during the index hospital admission.
Measured: From index hospital admission until discharge, assessed up to 90 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Dec 2023
- Study start5 Sep 2024
- Primary completion2 Mar 2028 (estimated)
- Study completion1 May 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Heart FailureStudies 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 3-arm parallel group RCT
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 939 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Johannes Grand
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Johannes Grand, Copenhagen University Hospital, Hvidovre
- Investigators
- Johannes Grand, MD, Phd, MPH, Principal investigator, Amager-Hvidovre Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06166654
- Sponsor's protocol ID
- DRAIN_AHF
- Other IDs
- 2024-510633-17-00
- Acronym
- DRAIN-AHF
- Status last verified
- Oct 2026
- First submitted
- 3 Dec 2023
- Last updated
- 27 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimal Diuretic Therapies for Acute Heart Failure With Volume Overload - A Randomized Clinical Trial
- ClinicalTrials.gov ID
- NCT06166654
- Acronym / sponsor ID
- DRAIN-AHF / DRAIN_AHF
- Conditions
- Acute Heart Failure
- Keywords
- acute heart failure, decongestion, diuretic
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 939 participants (estimated)
- Lead sponsor
- Johannes GrandUniversity, hospital or other
- Study start
- 5 Sep 2024 (actual)
- Primary completion
- 2 Mar 2028 (estimated)
- Study completion
- 1 May 2028 (estimated)
- First posted
- 12 Dec 2023 (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.
This trial aims to identify the best strategy for treating acute heart failure (AHF) with volume overload in patients at risk of diuretic resistance. It is a double-blinded, randomized, controlled, multicenter study comparing loop-diuretics combined with metolazone, loop-diuretics combined with acetazolamide, and loop-diuretics with matching placebos.
Eligible participants are adults aged 18 years or older who are hospitalized with AHF and have clinical signs of congestion and a risk of diuretic resistance.
The primary outcome is the number of days alive and out of hospital through day 30. Secondary outcomes are clinical benefit at 30 days, assessed using a hierarchical win ratio; days alive and out of hospital through day 90; and the duration of the index hospital admission.
The trial aims to enroll 939 participants across three treatment arms (313 per arm). The sample size is based on detecting a clinically relevant between-group difference of two days alive and out of hospital through day 30, with 80% power and adjustment for comparisons between the three groups.
Detailed description
Intravenous loop diuretics remain the cornerstone of treatment for acute heart failure with volume overload. However, a substantial proportion of patients experience an insufficient diuretic response, which may contribute to persistent congestion, prolonged hospitalization, and adverse clinical outcomes. Diuretic resistance may arise from several mechanisms, including reduced delivery of diuretics to their site of action, impaired renal function, and compensatory sodium reabsorption in nephron segments not targeted by loop diuretics.
Sequential nephron blockade represents a potential strategy to overcome diuretic resistance by combining diuretics acting at different sites of the nephron. Acetazolamide inhibits carbonic anhydrase in the proximal tubule, thereby reducing proximal sodium bicarbonate reabsorption and increasing sodium delivery to downstream nephron segments. Metolazone is a thiazide-like diuretic that inhibits sodium-chloride cotransport in the distal convoluted tubule, potentially counteracting compensatory distal sodium reabsorption during loop diuretic treatment.
Although both approaches may enhance natriuresis and facilitate decongestion, they differ in their mechanisms of action, electrolyte effects, and potential adverse events. Direct randomized comparisons of these strategies in patients hospitalized with acute heart failure are limited, and uncertainty remains regarding their relative clinical effectiveness and safety.
This trial is designed to address this evidence gap by directly comparing proximal and distal tubular diuretic strategies as adjuncts to intravenous loop diuretic therapy. The findings may help establish the optimal pharmacological approach to decongestion in patients with acute heart failure who are at risk of diuretic resistance.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- 3-arm parallel group RCT
| Arm | Type | Receives |
|---|---|---|
| Acetazolamide | Active comparator | Drug: AcetazolamideAcetazolamide 500 mg IV at randomization (day 0) and on the next three mornings (days 1, 2 and 3), with a matching placebo-metolazone tablet at each administration. The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines. |
| Metolazone | Active comparator | Drug: Metolazone 2.5 MGMetolazone 2.5 mg orally at randomization (day 0) and on the next three mornings (days 1, 2 and 3), with a matching placebo-acetazolamide injection at each administration. The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines. |
| Placebo | Placebo comparator | Other: Double-placeboMatching placebo-acetazolamide injection and placebo-metolazone tablet at randomization (day 0) and on the next three mornings (days 1, 2 and 3), in addition to usual care with loop-diuretics (SGLT2 inhibitors are allowed). The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Age ≥ 18 years
- Acute hospital admission with a clinical diagnosis of acute heart failure with volume overload.
- Display risk of diuretic resistance, characterized by:
- Clinical signs of congestion, indicated by one or more of the following: pitting peripheral edema, ascites, elevated jugular venous pressure, or radiological/ultrasonic evidence of pulmonary congestion.
Key exclusion criteria (8 listed)
- Acute coronary syndrome
- Systolic blood pressure <85 mmHg
- Use of renal replacement therapy or ultrafiltration in-hospital before study inclusion
- Treatment with acetazolamide or metolazone during the index hospitalization prior to randomization
- Known allergy to any of the used drugs
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 |
|---|---|---|
| AcetazolamideAcetazolamide 500 mg IV at randomization (day 0) and on the next three mornings (days 1, 2 and 3), with a matching placebo-metolazone tablet at each administration. The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines. | Drug | Acetazolamide |
| Metolazone 2.5 MGMetolazone 2.5 mg orally at randomization (day 0) and on the next three mornings (days 1, 2 and 3), with a matching placebo-acetazolamide injection at each administration. The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines. | Drug | Metolazone |
| Double-placeboMatching placebo-acetazolamide injection and placebo-metolazone tablet at randomization (day 0) and on the next three mornings (days 1, 2 and 3), in addition to usual care with loop-diuretics (SGLT2 inhibitors are allowed). The intervention phase does not exceed 72 hours and is stopped earlier at complete decongestion, discharge, or protocol-defined stopping criteria. Loop-diuretic treatment follows clinical assessment and current guidelines. | Other | Placebo |
Primary outcome
Days alive and out of hospital through day 30
Time frame: 30 days
Number of days alive and out of hospital during the 30-day period from inclusion. A return visit to the emergency department with discharge on the same day counts as one day in hospital.
3 secondary outcomes
Clinical benefit at 30 days assessed using a hierarchical win ratio
Time frame: 30 days
Days alive and out of hospital through day 90
Time frame: 90 days
Duration of the index hospital admission
Time frame: From index hospital admission until discharge, assessed up to 90 days
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Oct 2026.
- 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.
Sandra Tonning, MD contact
Johannes Grand, MD, Phd, MPH principal investigator
Amager-Hvidovre Hospital
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Acetazolamide and Metolazone 2.5 MG in people with Acute Heart Failure, run by Johannes Grand at 6 sites 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 6 inclusion and 8 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: looking for participants now, as of the sponsor's last update on 27 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Johannes Grand, MD, Phd, MPH (+4535452121, johannes.grand@regionh.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Days alive and out of hospital through day 30 (time frame: 30 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 27 Oct 2026.