PROVOCATION Trial - PROphylactic intraVenOus Hydration for Contrast Agent Toxicity PreventION

Kidney Failure, Acute Clinical Trial

Official title:

PROVOCATION Trial - PROphylactic intraVenOus Hydration for Contrast Agent Toxicity PreventION

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00130598
• Other study ID #: PROVOCATION Trial
• Secondary ID: 23.0505.0132005D
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: August 12, 2005
• Last updated: March 4, 2010
• Start date: June 2005
• Est. completion date: December 2009

Study information

• Verified date: March 2010
• Source: University Hospital, Basel, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Health authority: Switzerland: Swissmedic
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 258
• Est. completion date: December 2009
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Acute Kidney Injury
• Kidney Failure, Acute
• Renal Insufficiency

Intervention

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.

Locations

Country	Name	City	State
Italy	Centro Cardiologico Monzino	Milano
Switzerland	University Hospital of Basel	Basel
Switzerland	Kantonsspital Liestal - Universitätskliniken	Liestal

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Basel, Switzerland	Swiss National Science Foundation

Countries where clinical trial is conducted

Italy,  Switzerland, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Decrease in glomerular filtration rate (GFR) within 48 hours. GFR is calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation.		48 hours	No
Secondary	Development of contrast nephropathy, defined as an increase >=25% in the baseline serum creatinine concentration within 48 hours		48 hours	No
Secondary	Development of contrast nephropathy, defined as an increase >=44umol/l in serum creatinine concentration within 48 hours		48 hours	No
Secondary	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		48 hours	No
Secondary	Postcontrast increase in serum cystatin C at day 1 and 2		48 hours	No
Secondary	In-hospital morbidity (nonfatal myocardial infarction) and mortality		60 days	No
Secondary	Dialysis dependency		12 months	No
Secondary	Length of stay		60 days	No
Secondary	Total costs of hospitalization		60 days	No
Secondary	3-/12-month mortality		12 months	No
Secondary	3-/12-month hospitalization for cardiac causes		12 months	No
Secondary	GFR at 3 and 12 months		12 months	No

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