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Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics in Patients With Decompensated Heart Failure (CLOROTIC)

Primary Purpose

Heart Failure

Status
Completed
Phase
Phase 3
Locations
Spain
Study Type
Interventional
Intervention
hydrochlorothiazide
Placebo
Sponsored by
Spanish Society of Internal Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring Heart Failure, Diuretics, Diuretic resistance

Eligibility Criteria

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

Inclusion Criteria:

  • History of chronic heart failure
  • Admission for acute decompensated heart failure
  • There is no prespecified inclusion criterion with respect to heart failure etiology and/or ejection fraction
  • Receipt of an oral loop diuretic for at least 1 month before hospitalization, at a dose between 80 mg and 240 mg daily in the case of furosemide and an equivalent dose in the case of a different loop diuretic (20 mg of torasemide or 1 mg of bumetanide was considered to be equivalent to 40 mg of furosemide)

Exclusion Criteria:

  • Other etiologies of fluid overload different from heart failure
  • Hyponatremia: any symptomatic sodium value or a sodium level below 125mmol/l
  • Unstable patients: acute coronary syndrome, cardiogenic shock or ICU admission.
  • Patients requiring inotropic agents or renal replacement therapies
  • Life expectancy < 6 months
  • Prior treatment with thiazide-type diuretics
  • Aldosterone antagonists are permitted if the patient had been taking them on a long-term basis (at least 30 days before randomisation)
  • Pregnancy or breastfeeding period
  • Active alcoholism and/or other substance abuse

Sites / Locations

  • Internal Medicine Service, Hospital d'Olot (Girona)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Loop plus thiazide-type diuretic

Loop diuretic plus placebo

Arm Description

Loop diuretic plus hydrochlorothiazide

Loop diuretic plus placebo

Outcomes

Primary Outcome Measures

Changes in body weight
Bodyweight will be measured every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Changes in body weight measurements: the mean of weight lost every 24 hours and the total weight lost from baseline to the 5th day of hospitalisation. Participants will be followed for the duration of hospital stay, an expected average of 9 days.
Patient-reported dyspnea
Patient-reported dyspnea is assessed every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Patient-reported dyspnea is assessed with the use of a visual-analogue scale (VAS) and the Linker 7 point scale. Changes in patient-reported dyspnea: changes in the dyspnea scales from baseline to the 5th day of hospitalisation.

Secondary Outcome Measures

Diuresis
Worsening renal function
Renal function will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Renal function is assessed with the serum creatinine level. Worsening renal function is defined as an increase in the serum creatinine level of more than 0.3 mg/dl at any time during hospitalisation Participants will be followed for the duration of hospital stay, an expected average of 9 days.
Changes in electrolyte levels (sodium and potassium)
Electrolyte levels (sodium and potassium) will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Electrolyte levels are assessed with the serum sodium and potassium levels. Participants will be followed for the duration of hospital stay, an expected average of 9 days.
Metrics of diuretic response
weight loss and net fluid loss per mg of furosemide
Mortality (all-cause and heart failure)
Mortality (all-cause and heart failure) at 30 and 90days post-discharge
Rehospitalization (all-cause and heart failure)
Rehospitalization (all-cause and heart failure) at 30 and 90days post-discharge

Full Information

First Posted
June 28, 2012
Last Updated
September 30, 2022
Sponsor
Spanish Society of Internal Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT01647932
Brief Title
Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics in Patients With Decompensated Heart Failure
Acronym
CLOROTIC
Official Title
Safety and Efficacy of the Combination of Loop Diuretics With Thiazide-type Diuretics in Patients With Decompensated Heart Failure: a Double-blind, Randomized, Placebo-controlled Trial (CLOROTIC Trial).
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
October 2014 (undefined)
Primary Completion Date
December 15, 2019 (Actual)
Study Completion Date
December 15, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Spanish Society of Internal Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to determine whether a combined diuretic therapy (loop diuretics with thiazide-type diuretics) is more effective (in terms of improving fluid overload symptoms) among patients with decompensated heart failure in comparison with loop diuretic alone.
Detailed Description
Volume overload is an important clinical target in heart failure management, typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via "sequential nephron blockade," first described more than 40 years ago. Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. Combination diuretic therapy using any of several thiazide-type diuretics can more than double daily urine sodium excretion to induce weight loss and edema resolution. To our knowledge there are no clinical trials designed to prove the efficacy and safety of combined diuretic therapy (a commonly used therapy) among patients with decompensated heart failure.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure
Keywords
Heart Failure, Diuretics, Diuretic resistance

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
232 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Loop plus thiazide-type diuretic
Arm Type
Active Comparator
Arm Description
Loop diuretic plus hydrochlorothiazide
Arm Title
Loop diuretic plus placebo
Arm Type
Placebo Comparator
Arm Description
Loop diuretic plus placebo
Intervention Type
Drug
Intervention Name(s)
hydrochlorothiazide
Intervention Description
hydrochlorothiazide according to clearance of creatinine; >50ml/min 25mg daily, 20-50ml/min 50mg daily amd <20ml/min 100mg daily.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo according to clearance of creatinine; >50ml/min 1/2 pill daily, 20-50ml/min 1 pill daily amd <20ml/min 2 pills daily.
Primary Outcome Measure Information:
Title
Changes in body weight
Description
Bodyweight will be measured every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Changes in body weight measurements: the mean of weight lost every 24 hours and the total weight lost from baseline to the 5th day of hospitalisation. Participants will be followed for the duration of hospital stay, an expected average of 9 days.
Time Frame
Bodyweight will be measured every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge.
Title
Patient-reported dyspnea
Description
Patient-reported dyspnea is assessed every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Patient-reported dyspnea is assessed with the use of a visual-analogue scale (VAS) and the Linker 7 point scale. Changes in patient-reported dyspnea: changes in the dyspnea scales from baseline to the 5th day of hospitalisation.
Time Frame
Patient-reported dyspnea is assessed every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge.
Secondary Outcome Measure Information:
Title
Diuresis
Time Frame
24-hour diuresis will be quantified every 24 hours (during hospitalisation) from the 1st day until the 4th day of hospitalisation.
Title
Worsening renal function
Description
Renal function will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Renal function is assessed with the serum creatinine level. Worsening renal function is defined as an increase in the serum creatinine level of more than 0.3 mg/dl at any time during hospitalisation Participants will be followed for the duration of hospital stay, an expected average of 9 days.
Time Frame
Renal function will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge.
Title
Changes in electrolyte levels (sodium and potassium)
Description
Electrolyte levels (sodium and potassium) will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Electrolyte levels are assessed with the serum sodium and potassium levels. Participants will be followed for the duration of hospital stay, an expected average of 9 days.
Time Frame
Electrolyte levels (sodium and potassium) will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge.
Title
Metrics of diuretic response
Description
weight loss and net fluid loss per mg of furosemide
Time Frame
weight loss and net fluid loss per mg of furosemide
Title
Mortality (all-cause and heart failure)
Description
Mortality (all-cause and heart failure) at 30 and 90days post-discharge
Time Frame
Mortality (all-cause and heart failure) at 30 and 90days post-discharge
Title
Rehospitalization (all-cause and heart failure)
Description
Rehospitalization (all-cause and heart failure) at 30 and 90days post-discharge
Time Frame
Rehospitalization (all-cause and heart failure) at 30 and 90days post-discharge

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: History of chronic heart failure Admission for acute decompensated heart failure There is no prespecified inclusion criterion with respect to heart failure etiology and/or ejection fraction Receipt of an oral loop diuretic for at least 1 month before hospitalization, at a dose between 80 mg and 240 mg daily in the case of furosemide and an equivalent dose in the case of a different loop diuretic (20 mg of torasemide or 1 mg of bumetanide was considered to be equivalent to 40 mg of furosemide) Exclusion Criteria: Other etiologies of fluid overload different from heart failure Hyponatremia: any symptomatic sodium value or a sodium level below 125mmol/l Unstable patients: acute coronary syndrome, cardiogenic shock or ICU admission. Patients requiring inotropic agents or renal replacement therapies Life expectancy < 6 months Prior treatment with thiazide-type diuretics Aldosterone antagonists are permitted if the patient had been taking them on a long-term basis (at least 30 days before randomisation) Pregnancy or breastfeeding period Active alcoholism and/or other substance abuse
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joan Carles Trullas, MD, PhD
Organizational Affiliation
Heart Failure Study Group, Spanish Society of Internal Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Internal Medicine Service, Hospital d'Olot (Girona)
City
Olot
State/Province
Girona
ZIP/Postal Code
17800
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
21029871
Citation
Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010 Nov 2;56(19):1527-34. doi: 10.1016/j.jacc.2010.06.034.
Results Reference
background
PubMed Identifier
25560378
Citation
ter Maaten JM, Valente MA, Damman K, Hillege HL, Navis G, Voors AA. Diuretic response in acute heart failure-pathophysiology, evaluation, and therapy. Nat Rev Cardiol. 2015 Mar;12(3):184-92. doi: 10.1038/nrcardio.2014.215. Epub 2015 Jan 6.
Results Reference
background
PubMed Identifier
26576715
Citation
Trullas JC, Morales-Rull JL, Casado J, Freitas Ramirez A, Manzano L, Formiga F; CLOROTIC investigators. Rationale and Design of the "Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC) Trial:" A Double-Blind, Randomized, Placebo-Controlled Study to Determine the Effect of Combined Diuretic Therapy (Loop Diuretics With Thiazide-Type Diuretics) Among Patients With Decompensated Heart Failure. J Card Fail. 2016 Jul;22(7):529-36. doi: 10.1016/j.cardfail.2015.11.003. Epub 2015 Nov 11.
Results Reference
background
PubMed Identifier
24930082
Citation
Trullas JC, Morales-Rull JL, Formiga F. [Diuretic therapy in acute heart failure]. Med Clin (Barc). 2014 Mar;142 Suppl 1:36-41. doi: 10.1016/S0025-7753(14)70081-8. Spanish.
Results Reference
background
PubMed Identifier
30610440
Citation
Trullas JC, Casado J, Morales-Rull JL, Formiga F, Conde-Martel A, Quiros R, Epelde F, Gonzalez-Franco A, Manzano L, Montero-Perez-Barquero M. Prevalence and outcome of diuretic resistance in heart failure. Intern Emerg Med. 2019 Jun;14(4):529-537. doi: 10.1007/s11739-018-02019-7. Epub 2019 Jan 4.
Results Reference
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Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics in Patients With Decompensated Heart Failure

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