Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis (CRYSTMAS)

• ClinicalTrials.gov Identifier: NCT00464204
• Recruitment Status: Completed
• First Posted: April 23, 2007
• Results First Posted: August 2, 2011
• Last Update Posted: January 11, 2012
• Sponsor: Fresenius Kabi
• Information provided by (Responsible Party): Fresenius Kabi

Tracking Information

• First Submitted Date: April 20, 2007
• First Posted Date: April 23, 2007
• Results First Submitted Date: May 30, 2011
• Results First Posted Date: August 2, 2011
• Last Update Posted Date: January 11, 2012
• Study Start Date: July 2007
• Actual Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 4, 2011)

Amount of Study Drug Required to Achieve Initial Hemodynamic Stabilization [ Time Frame: until hemodynamic stabilization (up to 48 hours) ]

Initial hemodynamic stabilization (HDS) was defined as normalization of mean arterial pressure (MAP) and at least two of the three parameters central venous pressure (CVP), urine output and central venous oxygen saturation and maintaining this normalization over a period of four hours, with no increase in the infusion of vasopressors, or ionotropic therapy and with no more than 1 L of additional study drug administration within these four hours.

Original Primary Outcome Measures (submitted: April 20, 2007)

• Amount of Study Drug Required to Achieve Initial Hemodynamic Stabilization
• Amount of enteral calories during 7 days after hemodynamic stabilization

Current Secondary Outcome Measures (submitted: July 4, 2011)

• Time From Start of Fluid Resuscitation With Study Drug to the Initial Hemodynamic Stabilization [ Time Frame: until hemodynamic stabilization (up to 48 hours) ]
  Time from start of fluid resuscitation with study drug to the initial hemodynamic stabilization
• Quantity of Study Drug in 4 Days [ Time Frame: 4 days ]
  Total quantity of study drug infused over four consecutive days in the ICU
• Time From Start of Study Drug to Start of Enteral Nutrition in the Subgroup of Patients Who Received Enteral Nutrition [ Time Frame: Until start of enteral nutrition (up to 48 hours) ]
  Time from start of fluid resuscitation with study drug to start of enteral nutrition.
• Time From Start of Fluid Resuscitation With Study Drug to Start of Enteral Nutrition After Hemodynamic Stabilization [ Time Frame: up to 48 hours ]
  Administration of enteral nutrition before initial hemodynamic stabilization was ignored in this analysis.
• Total Amount of Enteral Calories During the First Seven Days of Enteral Nutrition [ Time Frame: 7 days ]
  This amount will be calculated from start of enteral nutrition until 7 am of day 8
• Length of Stay in the Intensive Care Unit (ICU) [ Time Frame: Until discharge from ICU (up to day 90) ]
  Length of stay was analysed in two approaches. First, it was calculated and analysed only for patients who did not die before end of study of the individual patient. As a sensitivity analysis, the analysis was carried out including patients who died with the maximum possible length of stay (i.e., the worst possible value).
• Length of Stay in the ICU [ Time Frame: Until discharge from ICU (up to Day 90) ]
  Length of stay was analysed in two approaches. First, it was calculated and analysed only for patients who did not die before end of study of the individual patient. As a sensitivity analysis, the analysis was carried out including patients who died with the maximum possible length of stay (i.e., worst possible value).
• Length of Stay in the Hospital [ Time Frame: Until discharge from hospital (up to day 90) ]
  Length of stay was analysed in two approaches. First, it was calculated and analysed only for patients who did not die before end of study of the individual patient. As a sensitivity analysis, the analysis was carried out including patients who died with the maximum possible length of stay (i.e., the worst possible value).
• Area Under the Curve (AUC) of Sepsis-related Organ Failure Assessment (SOFA) Score Per Day From Screening to Day 4 [ Time Frame: From Screening to Day 4 ]
  The Sepsis-related Organ Failure Assessment (SOFA) score in this study is reported for entire days, not for exact time points on a day. Potentially, more than one SOFA score may be available for the same day. In this case, the mean of the respective total scores was used for that day for calculation of Area Under the Curve (AUC). The SOFA score includes sub-scores for Respiration, Coagulation, Liver, Cardiovascular, Central Nervous System and Renal function and may range from 0 (worst outcome) to 4 (best outcome).

Original Secondary Outcome Measures (submitted: April 20, 2007)

• Time from start of fluid resuscitation with study drug to hemodynamic stabilization
• Quantity of Study Drug in 4 Days
• Time from start of study drug to start of enteral nutrition
• Length of stay in hospital and ICU
• SOFA score

Current Other Pre-specified Outcome Measures (submitted: August 8, 2011)

• Mortality [ Time Frame: From Screening to end of Follow-up ]
  Mortality was reported for the time period from Screening until the end of follow-up.
• Changes in Renal Function: 1. Acute Renal Failure (ARF) at Any Time After Screening [ Time Frame: From screening to end of follow-up (up to day 90) ]
  Acute Renal Failure (ARF) was defined as a two fold increase in serum concentration over the value at screening at any time after screening.
• Changes in Renal Function: 2. Acute Kidney Injury Network (AKIN) Classification [ Time Frame: From screening to end of follow-up ]
  Acute Kidney Injury Network (AKIN) Classification in this study is based on serum creatinine values and renal replacement therapy, i.e. ignoring criteria based on urine output, as fulfilment of urine output criteria cannot be determined from the data collected in the study. AKIN ranges from stage 1 to stage 3 (worst outcome). Stages differ in serum creatinine increase. Stage 1: Increase ≥ 0.3mg/dL or ≥ 150%-200% from reference; Stage 2: Increase ≥ 200%-300% from reference; Stage 3: Increase >300% from reference with an acute increase of at least 0.5mg/dL or renal replacement therapy.
• Changes in Renal Function: 3. Risk, Injury, Failure, Loss, End-stage Kidney Disease (RIFLE) Classification [ Time Frame: From screening to end of follow-up ]
  Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) Classification in this study is based on serum creatinine values and renal replacement therapy, i.e. ignoring criteria based on urine output, as fulfilment of urine output criteria cannot be determined from the data collected in the study. RIFLE comprises five categories: Risk (R), Injury (I), Failure (F), Loss (L), End-stage kidney disease (E) (worst outcome). R, I and F are based on increase in serum creatinine. L and E are based on administration of renal replacement therapy.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis
• Official Title: Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis
• Brief Summary: The rapidity and the quality of fluid resuscitation in patients with severe sepsis are important factors for the prevention of secondary multi-organ failure. Vascular filling may also have an impact on tolerability of enteral nutrition. The earliness and quantity of calories provided by enteral nutrition may have an impact on morbidity and mortality. This study will asses the effects of volume expansion on hemodynamics and tolerability of enteral nutrition in patients with severe sepsis. A Data Monitoring Committee will review regularly safety data of the study.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Sepsis

Intervention

• Drug: 6 % Hydroxyethylstarch 130/0.4 = "Voluven®"
  Voluven® was administered intravenously. Voluven® rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day on the second to fourth days, according to patient needs.
  Other Name: Voluven®
• Drug: 0.9 % NaCl
  NaCl 0.9 % was administered intravenously. NaCl 0.9% rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day, according to patient needs.

Study Arms

• Experimental: Voluven® Arm
  Intervention: Drug: 6 % Hydroxyethylstarch 130/0.4 = "Voluven®"
• Active Comparator: 0.9 % NaCl
  Intervention: Drug: 0.9 % NaCl

• Publications *: Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, Maizel J, Forceville X, Feissel M, Hasselmann M, Heininger A, Van Aken H. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: the CRYSTMAS study. Crit Care. 2012 May 24;16(3):R94. doi: 10.1186/cc11358.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 4, 2011): 196
• Original Enrollment (submitted: April 20, 2007): 180
• Actual Study Completion Date: December 2010
• Actual Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Severe sepsis
• Requirement for fluid resuscitation

Exclusion Criteria:

• serum creatinine > 300µmol/L
• Chronic renal failure
• Anuria lasting more than 4 hours
• Requirement for renal support

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Germany

Administrative Information

• NCT Number: NCT00464204
• Other Study ID Numbers: 06-HE06-01; 2006-004350-25 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Fresenius Kabi
• Study Sponsor: Fresenius Kabi
• Collaborators: Not Provided

Investigators

• Study Chair: Bertrand Guidet, Prof., MD; Hôpital St Antoine, Réanimation Médicale

• PRS Account: Fresenius Kabi
• Verification Date: August 2011