PROVOCATION Trial - PROphylactic intraVenOus Hydration for Contrast Agent Toxicity PreventION

• ClinicalTrials.gov Identifier: NCT00130598
• Recruitment Status: Completed
• First Posted: August 15, 2005
• Last Update Posted: March 5, 2010
• Sponsor: University Hospital, Basel, Switzerland
• Collaborator: Swiss National Science Foundation
• Information provided by: University Hospital, Basel, Switzerland

Study Description

Brief Summary:

Contrast nephropathy (CN) remains a common complication of radiographic procedures and an important cause of hospital-acquired acute renal failure. Only hydration with saline is uniformly accepted and used in clinical practice as a cornerstone for the prevention of CN. But the optimal preventive strategy for CN is not known. Sodium bicarbonate might be even more effective than hydration with sodium chloride for prophylaxis of CN. Therefore the aim of the study is to evaluate the efficacy of two regimens of sodium bicarbonate compared with a prolonged infusion of sodium chloride in the prevention of CN.

Primary endpoint: Decrease in glomerular filtration rate (GFR) within 48 hours.

Condition or disease	Intervention/treatment	Phase
Kidney Failure, Acute	Drug: NaCl 0.9% i.v. or NaBic 1.4% i.v. or NaBic 1.4% i.v. + NaBic p.o. (Nephrotrans®)	Phase 2; Phase 3

Detailed Description:

Background: Contrast nephropathy (CN) remains a common complication of radiographic procedures and an important cause of hospital-acquired acute renal failure, which contributes to morbidity and mortality during hospitalization, as well as costs of health care. Many previous strategies to prevent CN (such as N-acetylcysteine, aminophylline, fenoldopam, hemofiltration) have been unsuccessful or at least controversial. Only hydration with saline is uniformly accepted and used in clinical practice as cornerstone for the prevention of CN. But the optimal preventive strategy for CN is not known. According to a recent study, periprocedural hydration with sodium bicarbonate might be even more effective than hydration with sodium chloride for prophylaxis of CN. Such a preventive hydration with sodium bicarbonate should be compared with the gold standard of hydration with saline (24-h hydration period). This has not been evaluated so far. Given its high oral bioavailability, sodium bicarbonate could be administered even orally instead of a prolonged infusion. An effective short-term regimen would be highly attractive in clinical practice including outpatient procedures.

Aim: To evaluate the efficacy of two regimens of sodium bicarbonate compared with a prolonged infusion of sodium chloride in the prevention of CN.

Primary endpoint: Decrease in glomerular filtration rate (GFR) within 48 hours. GFR is calculated using the abbreviated Modification of Diet in Renal Disease Study equation. Secondary endpoints: Development of contrast nephropathy defined by increase in serum creatinine concentration of at least 44umol/l within 48 hours, an increase >=25% in the baseline serum creatinine concentration within 48 hours, or defined as an increase >=25% in the baseline serum cystatin C concentration or an increase >=0.35mg/l in serum cystatin C concentration within 48 hours; increase in serum cystatin C level at day 1 and 2, in-hospital morbidity (nonfatal myocardial infarction) and mortality, dialysis, length of stay, total costs of hospitalization, 3-/12-month mortality, 3-/12-month hospitalization for cardiac causes, and GFR at 3 and 12 months.

Patients and Methods: This randomized, controlled open-label trial is designed to enroll 258 patients at increased risk for CN because of renal dysfunction undergoing intraarterial or intravenous radiographic contrast procedures. Patients will be randomly assigned 1:1:1 with the use of sealed envelopes into 3 groups (block randomisation for intraarterial and intravenous radiographic contrast procedures) :

1. a control group: patients receive a preventive hydration with 154mEq/l saline at an ongoing rate of 1ml/kg per hour of at least 12 hours prior and after the procedure.
2. a group with 7h-sodium bicarbonate (according to the regimen used in a recently published study (slightly modified)14): before contrast a bolus of 3ml/kg NaHCO3 166mEq/l for one hour, followed by an infusion of NaHCO3 166mEq/l with a rate of 1ml/kg per hour until 6h after contrast.
3. a group with short-term sodium bicarbonate: NaHCO3 166mEq/l (3ml/kg; patients with a body weight above 100kg 300ml) as a bolus 20 minutes before contrast; additionally ingestion of Nephrotrans® (500mg NaHCO3/capsule: 1 capsule/10kg) with 1-2 dl of San Pellegrino® non-sparkling mineral water at the start of the infusion. Ingestion of 500ml San Pellegrino® non-sparkling mineral water in the first 6 hours after contrast.

Expected results: It is the researchers' hypothesis that a short-term periprocedural preventive hydration with sodium bicarbonate will be non-inferior to the regimen of long-term hydration with sodium bicarbonate. The long-term regimen with sodium bicarbonate is expected to be superior to the standard i.v. regimen with sodium chloride.

Significance: Given the significant morbidity and mortality associated with acute renal failure due to contrast media as well as the widespread use of contrast media in an ambulant setting for diagnostic and therapeutical procedures, preventive short-term hydration with sodium bicarbonate could represent a major advance in clinical medicine.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 258 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: PROVOCATION Trial - PROphylactic intraVenOus Hydration for Contrast Agent Toxicity PreventION
• Study Start Date: June 2005
• Actual Primary Completion Date: December 2009
• Actual Study Completion Date: December 2009

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 1; control group: patients receive a preventive hydration with 154mEq/l saline at an ongoing rate of 1ml/kg per hour of at least 12 hours prior and after the procedure.	Drug: NaCl 0.9% i.v. or NaBic 1.4% i.v. or NaBic 1.4% i.v. + NaBic p.o. (Nephrotrans®); control group: preventive hydration with 154mEq/l saline at 1ml/kg per hour of 12 hours prior and after the procedure. 7h-sodium bicarbonate: before contrast 3ml/kg NaHCO3 166mEq/l for one hour, followed by NaHCO3 166mEq/l (1ml/kg per hour until 6h after contrast). short-term sodium bicarbonate: NaHCO3 166mEq/l (3ml/kg) as a bolus 20 minutes before contrast; ingestion of Nephrotrans® (500mg NaHCO3/capsule: 1 capsule/10kg) with 1-2 dl non-sparkling mineral water at the start of the infusion. Ingestion of non-sparkling mineral water in the first 6 hours after contrast.; Other Names: NaCl 0.9% Braun®; NaBic 1.4% Bichsel®; Nephrotrans®
Active Comparator: 2; 7h-sodium bicarbonate (according to the regimen used in a recently published study (slightly modified)14): before contrast a bolus of 3ml/kg NaHCO3 166mEq/l for one hour, followed by an infusion of NaHCO3 166mEq/l with a rate of 1ml/kg per hour until 6h after contrast.	Drug: NaCl 0.9% i.v. or NaBic 1.4% i.v. or NaBic 1.4% i.v. + NaBic p.o. (Nephrotrans®); control group: preventive hydration with 154mEq/l saline at 1ml/kg per hour of 12 hours prior and after the procedure. 7h-sodium bicarbonate: before contrast 3ml/kg NaHCO3 166mEq/l for one hour, followed by NaHCO3 166mEq/l (1ml/kg per hour until 6h after contrast). short-term sodium bicarbonate: NaHCO3 166mEq/l (3ml/kg) as a bolus 20 minutes before contrast; ingestion of Nephrotrans® (500mg NaHCO3/capsule: 1 capsule/10kg) with 1-2 dl non-sparkling mineral water at the start of the infusion. Ingestion of non-sparkling mineral water in the first 6 hours after contrast.; Other Names: NaCl 0.9% Braun®; NaBic 1.4% Bichsel®; Nephrotrans®
Active Comparator: 3; short-term sodium bicarbonate: NaHCO3 166mEq/l (3ml/kg; patients with a body weight above 100kg 300ml) as a bolus 20 minutes before contrast; additionally ingestion of Nephrotrans® (500mg NaHCO3/capsule: 1 capsule/10kg) with 1-2 dl of San Pellegrino® non-sparkling mineral water at the start of the infusion. Ingestion of 500ml San Pellegrino® non-sparkling mineral water in the first 6 hours after contrast.	Drug: NaCl 0.9% i.v. or NaBic 1.4% i.v. or NaBic 1.4% i.v. + NaBic p.o. (Nephrotrans®); control group: preventive hydration with 154mEq/l saline at 1ml/kg per hour of 12 hours prior and after the procedure. 7h-sodium bicarbonate: before contrast 3ml/kg NaHCO3 166mEq/l for one hour, followed by NaHCO3 166mEq/l (1ml/kg per hour until 6h after contrast). short-term sodium bicarbonate: NaHCO3 166mEq/l (3ml/kg) as a bolus 20 minutes before contrast; ingestion of Nephrotrans® (500mg NaHCO3/capsule: 1 capsule/10kg) with 1-2 dl non-sparkling mineral water at the start of the infusion. Ingestion of non-sparkling mineral water in the first 6 hours after contrast.; Other Names: NaCl 0.9% Braun®; NaBic 1.4% Bichsel®; Nephrotrans®

Outcome Measures

Primary Outcome Measures :

1. Decrease in glomerular filtration rate (GFR) within 48 hours. GFR is calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation. [ Time Frame: 48 hours ]

Secondary Outcome Measures :

1. Development of contrast nephropathy, defined as an increase >=25% in the baseline serum creatinine concentration within 48 hours [ Time Frame: 48 hours ]
2. Development of contrast nephropathy, defined as an increase >=44umol/l in serum creatinine concentration within 48 hours [ Time Frame: 48 hours ]
3. Development of contrast nephropathy, defined as an increase >=25% in the baseline serum cystatin C concentration or an increase >=0.35mg/l in serum cystatin C concentration within 48 hours [ Time Frame: 48 hours ]
4. Postcontrast increase in serum cystatin C at day 1 and 2 [ Time Frame: 48 hours ]
5. In-hospital morbidity (nonfatal myocardial infarction) and mortality [ Time Frame: 60 days ]
6. Dialysis dependency [ Time Frame: 12 months ]
7. Length of stay [ Time Frame: 60 days ]
8. Total costs of hospitalization [ Time Frame: 60 days ]
9. 3-/12-month mortality [ Time Frame: 12 months ]
10. 3-/12-month hospitalization for cardiac causes [ Time Frame: 12 months ]
11. GFR at 3 and 12 months [ Time Frame: 12 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• All patients admitted with renal dysfunction (baseline serum creatinine level above the upper limit of normal of the serum creatinine [>93umol/l for women and >117umol/l for men] or GFR <60ml/min [GFR calculated using the abbreviated MDRD study equation]) scheduled to undergo an intraarterial or intravenous radiographic contrast procedure within the next 24 hours.

Exclusion Criteria:

• Age <18 years
• Preexisting dialysis
• Allergy to radiographic contrast
• Pregnancy (women < 50 years: pregnancy test required)
• Severe heart failure (New York Heart Association [NYHA] III-IV)
• N-acetylcysteine </= 24 hours before contrast
• Clinically vulnerable condition requiring continuous fluid therapy e.g. severe sepsis

Contacts and Locations

Locations

Italy

Centro Cardiologico Monzino

Milano, Italy, 20138

Switzerland

University Hospital of Basel

Basel, Switzerland, 4031

Kantonsspital Liestal - Universitätskliniken

Liestal, Switzerland, 4100

Sponsors and Collaborators

University Hospital, Basel, Switzerland

Swiss National Science Foundation

Investigators

• Principal Investigator: Christian Mueller, Prof.; University Hospital of Basel

More Information

Additional Information:

Related Info 

Publications:

Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ, Bersin RM, Van Moore A, Simonton CA 3rd, Rittase RA, Norton HJ, Kennedy TP. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004 May 19;291(19):2328-34. doi: 10.1001/jama.291.19.2328.

Mueller C, Seidensticker P, Buettner HJ, Perruchoud AP, Staub D, Christ A, Buerkle G. Incidence of contrast nephropathy in patients receiving comprehensive intravenous and oral hydration. Swiss Med Wkly. 2005 May 14;135(19-20):286-90. doi: 10.4414/smw.2005.10938.

Mueller C, Buerkle G, Buettner HJ, Petersen J, Perruchoud AP, Eriksson U, Marsch S, Roskamm H. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med. 2002 Feb 11;162(3):329-36. doi: 10.1001/archinte.162.3.329.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Klima T, Christ A, Marana I, Kalbermatter S, Uthoff H, Burri E, Hartwiger S, Schindler C, Breidthardt T, Marenzi G, Mueller C. Sodium chloride vs. sodium bicarbonate for the prevention of contrast medium-induced nephropathy: a randomized controlled trial. Eur Heart J. 2012 Aug;33(16):2071-9. doi: 10.1093/eurheartj/ehr501. Epub 2012 Jan 19.

• Responsible Party: University Hospital, Basel, Switzerland, Christian Mueller, MD
• ClinicalTrials.gov Identifier: NCT00130598
• Other Study ID Numbers: PROVOCATION Trial; 23.05; 05.013; 2005DR3170
• First Posted: August 15, 2005
• Last Update Posted: March 5, 2010
• Last Verified: March 2010

Keywords provided by University Hospital, Basel, Switzerland:

contrast nephropathy; contrast media; renal dysfunction

Additional relevant MeSH terms:

Renal Insufficiency; Acute Kidney Injury; Kidney Diseases; Urologic Diseases