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Diuretic Versus Placebo in Pulmonary Embolism (DiPER)

Primary Purpose

Pulmonary Embolism With Right Ventricle Enlargement

Status
Unknown status
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Diuretics : Furosemide
Placebo
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Embolism With Right Ventricle Enlargement focused on measuring Pulmonary Embolism, Right Ventricle failure, Diuretics

Eligibility Criteria

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

Inclusion Criteria:

Patients aged 18 years and over with

  1. Symptomatic acute pulmonary embolism with first clinical symptoms within 15 days, and objectively confirmed by CT scan

  2. RV dysfunction (≥1 criterion) confirmed by elevated BNP value or echocardiography or spiral computed tomography of the chest:

    • Echocardiography

      o Right/Left ventricular end diastolic diameter > 1(apical or subcostal 4-chamber view)

    • Computed tomography

      o Right/Left short-axis diameter ratio>0.9 (transverse plane)

    • Positive Nt-proBNP (>600) or BNP>200 pg/mL

  3. One abnormal following PESI criteria

    • Heart Rate>110/min
    • Systolic blood pressure<100mmHg
    • Arterial oxyhemoglobin level<90% on room air or after 5 minutes of oxygen withdrawal.

Exclusion Criteria:

  • Cardiogenic shock requiring thrombolysis
  • Previous significant left ventricular insufficiency (LVEF<45%)
  • Systolic blood pressure<90mmHg at admission
  • Age ≤ 18 years
  • Pregnancy
  • No health insurance
  • Patients deprived of liberty or under legal protection
  • Creatinin clearance <30mL/min/m²
  • hypersensibility to furosemide or its excipients
  • functional renal insufficiency
  • Hepatic encephalopathy
  • Urinary tracks obstruction
  • Hypovolemia or dehydration.
  • Sever hypokalemia (K+ < 3mmol/L)
  • Severe hyponatremia (Na+ < 125mmol/L)
  • Ongoing hepatitis and hepatic insufficiency severe in patients with renal insufficiency or dialysis

Sites / Locations

  • Henri Mondor HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Diuretics

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Primary end point will be a combined clinical criterion, to reach the primary endpoint, patients have to meet all the following criteria: - Urine output> 0.5ml/kg/h - Normalization of clinical parameters of simplified PESI score
Normalization of clinical parameters of simplified PESI score : Heart Rate<110/min Systolic blood pressure≥100mmHg Arterial oxyhemoglobin level>90% on room air or after 5 minutes of oxygen withdrawal.

Secondary Outcome Measures

patients have to meet all the four following criteria: - Urine output> 0.5ml/kg/h over 24 hours - Normalization of clinical parameters of simplified PESI score - Urine output
Normalization of clinical parameters of simplified PESI score : Heart Rate<110/min Systolic blood pressure≥100mmHg Arterial oxyhemoglobin level>90% on room air or after 5 minutes of oxygen withdrawal.
- Composite criteria including death, need for catecholamine, cardiac arrest and mechanical ventilation during hospitalization and at 1 month from inclusion - NYHA score
o RV/LV ratio and decrease from baseline o Systolic pulmonary pressure and decrease from baseline o Tricuspid annular plane systolic expansion (TAPSE) at o Tricuspid annular plane systolic expansion (TAPSE) variation from baseline
RV/LV ratio (diameters and surfaces)
- NT-proBNP or BNP decrease at 24hours - Creatinin and liver enzymes variations at 24hours

Full Information

First Posted
October 16, 2014
Last Updated
October 18, 2017
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT02268903
Brief Title
Diuretic Versus Placebo in Pulmonary Embolism
Acronym
DiPER
Official Title
Diuretic Versus Placebo in Pulmonary Embolism With Right Ventricular Enlargement: a Double-blind Randomized Controlled Study
Study Type
Interventional

2. Study Status

Record Verification Date
October 2017
Overall Recruitment Status
Unknown status
Study Start Date
April 13, 2015 (Actual)
Primary Completion Date
April 2018 (Anticipated)
Study Completion Date
May 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Pulmonary Embolism (PE) is a frequent and severe disease with an annual incidence of about 75000 cases in France and a short-term mortality rate of about 10%. Death is usually related to an acute right ventricular (RV) failure due to the increase in right ventricular afterload. Treatment of PE with RV failure consists in fluid expansion and thrombolysis in case of shock. However several studies suggest that fluid expansion may worsen acute RV failure by increasing RV dilatation and ischemia and left ventricular compression by RV dilatation. Thus, current guidelines regarding PE treatment remain unclear about the use of fluid expansion. In a preliminary study published by our group, we showed that diuretic treatment in the setting of PE with RV dilatation is safe and is associated with an increase in urine output, a decrease in heart rate and an increase in SpO2 in normotensive patients with oliguria. This may be related to the decrease of ventricular interdependence and enhancement of both LV and RV function. The main objective of the study is to evaluate the 24-hours clinical benefit of furosemide in patients referred for acute PE with RV dilatation compared to placebo. The combination of urine output and sPESI clinical parameters reflects hemodynamic status. It is relevant as it indicates the disappearance of pre-shock symptoms and is therefore associated with a lower event risk. Thus, it allows early discharge of the patients from the intensive care unit.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Embolism With Right Ventricle Enlargement
Keywords
Pulmonary Embolism, Right Ventricle failure, Diuretics

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Diuretics
Arm Type
Active Comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Diuretics : Furosemide
Intervention Description
Furosemide 80mg in one single direct intra venous injection
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo in one single direct intra venous injection
Primary Outcome Measure Information:
Title
Primary end point will be a combined clinical criterion, to reach the primary endpoint, patients have to meet all the following criteria: - Urine output> 0.5ml/kg/h - Normalization of clinical parameters of simplified PESI score
Description
Normalization of clinical parameters of simplified PESI score : Heart Rate<110/min Systolic blood pressure≥100mmHg Arterial oxyhemoglobin level>90% on room air or after 5 minutes of oxygen withdrawal.
Time Frame
24 hours
Secondary Outcome Measure Information:
Title
patients have to meet all the four following criteria: - Urine output> 0.5ml/kg/h over 24 hours - Normalization of clinical parameters of simplified PESI score - Urine output
Description
Normalization of clinical parameters of simplified PESI score : Heart Rate<110/min Systolic blood pressure≥100mmHg Arterial oxyhemoglobin level>90% on room air or after 5 minutes of oxygen withdrawal.
Time Frame
48 hours
Title
- Composite criteria including death, need for catecholamine, cardiac arrest and mechanical ventilation during hospitalization and at 1 month from inclusion - NYHA score
Time Frame
In hospital and 1 month
Title
o RV/LV ratio and decrease from baseline o Systolic pulmonary pressure and decrease from baseline o Tricuspid annular plane systolic expansion (TAPSE) at o Tricuspid annular plane systolic expansion (TAPSE) variation from baseline
Description
RV/LV ratio (diameters and surfaces)
Time Frame
24 hours abd 1 month
Title
- NT-proBNP or BNP decrease at 24hours - Creatinin and liver enzymes variations at 24hours
Time Frame
24 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients aged 18 years and over with Symptomatic acute pulmonary embolism with first clinical symptoms within 15 days, and objectively confirmed by CT scan RV dysfunction (≥1 criterion) confirmed by elevated BNP value or echocardiography or spiral computed tomography of the chest: Echocardiography o Right/Left ventricular end diastolic diameter > 1(apical or subcostal 4-chamber view) Computed tomography o Right/Left short-axis diameter ratio>0.9 (transverse plane) Positive Nt-proBNP (>600) or BNP>200 pg/mL One abnormal following PESI criteria Heart Rate>110/min Systolic blood pressure<100mmHg Arterial oxyhemoglobin level<90% on room air or after 5 minutes of oxygen withdrawal. Exclusion Criteria: Cardiogenic shock requiring thrombolysis Previous significant left ventricular insufficiency (LVEF<45%) Systolic blood pressure<90mmHg at admission Age ≤ 18 years Pregnancy No health insurance Patients deprived of liberty or under legal protection Creatinin clearance <30mL/min/m² hypersensibility to furosemide or its excipients functional renal insufficiency Hepatic encephalopathy Urinary tracks obstruction Hypovolemia or dehydration. Sever hypokalemia (K+ < 3mmol/L) Severe hyponatremia (Na+ < 125mmol/L) Ongoing hepatitis and hepatic insufficiency severe in patients with renal insufficiency or dialysis
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jean-Luc DUBOIS-RANDE, PU-PH
Phone
(0)1 49 81 36 02
Ext
+33
Email
jean-luc.duboisrande@hmn.aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Romain GALLET, CCA
Phone
(0)1 49 81 36 02
Ext
+33
Email
romain.gallet@yahoo.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jean-Luc DUBOIS-RANDE, PU-PH
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Henri Mondor Hospital
City
Creteil
ZIP/Postal Code
94010
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jean-Luc DUBOIS-RANDE, PU-PH
Phone
(0)1 49 81 36 02
Ext
+33
Email
jean-luc.duboisrande@hmn.aphp.fr
First Name & Middle Initial & Last Name & Degree
Dalila SELMANE, CRA
Phone
(0)1 49 81 33 86
Ext
+33
Email
dalila.selmane@hmn.aphp.fr
First Name & Middle Initial & Last Name & Degree
Pascal LIM, PH

12. IPD Sharing Statement

Citations:
PubMed Identifier
11888976
Citation
Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002 Mar;121(3):877-905. doi: 10.1378/chest.121.3.877.
Results Reference
background
PubMed Identifier
1739960
Citation
Lee FA. Hemodynamics of the right ventricle in normal and disease states. Cardiol Clin. 1992 Feb;10(1):59-67.
Results Reference
background
PubMed Identifier
18757870
Citation
Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP; ESC Committee for Practice Guidelines (CPG). Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008 Sep;29(18):2276-315. doi: 10.1093/eurheartj/ehn310. Epub 2008 Aug 30.
Results Reference
background
PubMed Identifier
17210881
Citation
Perlroth DJ, Sanders GD, Gould MK. Effectiveness and cost-effectiveness of thrombolysis in submassive pulmonary embolism. Arch Intern Med. 2007 Jan 8;167(1):74-80. doi: 10.1001/archinte.167.1.74.
Results Reference
background
PubMed Identifier
8094768
Citation
Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira da Silva AM, Come PC, Lee RT, Parker JA, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet. 1993 Feb 27;341(8844):507-11. doi: 10.1016/0140-6736(93)90274-k.
Results Reference
background
PubMed Identifier
34632490
Citation
Lim P, Delmas C, Sanchez O, Meneveau N, Rosario R, Bouvaist H, Bernard A, Mansourati J, Couturaud F, Sebbane M, Coste P, Rohel G, Tardy B, Biendel C, Lairez O, Ivanes F, Gallet R, Dubois-Rande JL, Fard D, Chatelier G, Simon T, Paul M, Natella PA, Layese R, Bastuji-Garin S. Diuretic vs. placebo in intermediate-risk acute pulmonary embolism: a randomized clinical trial. Eur Heart J Acute Cardiovasc Care. 2022 Jan 12;11(1):2-9. doi: 10.1093/ehjacc/zuab082.
Results Reference
derived
PubMed Identifier
26002690
Citation
Gallet R, Meyer G, Ternacle J, Biendel C, Brunet A, Meneveau N, Rosario R, Couturaud F, Sebbane M, Lamblin N, Bouvaist H, Coste P, Maitre B, Bastuji-Garin S, Dubois-Rande JL, Lim P. Diuretic versus placebo in normotensive acute pulmonary embolism with right ventricular enlargement and injury: a double-blind randomised placebo controlled study. Protocol of the DiPER study. BMJ Open. 2015 May 22;5(5):e007466. doi: 10.1136/bmjopen-2014-007466.
Results Reference
derived

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Diuretic Versus Placebo in Pulmonary Embolism

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