Albumin To Enhance Recovery After Acute Kidney Injury

Study Overview
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Brief Summary
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Study objectives: To determine whether, in critically ill patients with Acute Kidney Injury requiring renal replacement therapy (AKI-RRT), randomization to receive intravenous hyperoncotic albumin 20-25% (100 mL X two doses) compared to control/placebo normal saline boluses (100 mL X two doses) given during RRT sessions, leads to: An increase in organ support-free days (primary outcome) at 28 days following randomization; and An increase in RRT-free days (principal secondary outcome) at 28 days following randomization.

Detailed Description
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Background: Severe Acute Kidney Injury that necessitates renal replacement therapy (AKI-RRT) is a frequent complication of critical illness and portends severe outcomes: high morbidity, an approximately 50% risk of in-hospital death, and increased healthcare resource utilization. Although life-saving when needed, RRT itself may contribute to the poor outcomes associated with AKI-RRT. Since RRT treatments frequently cause hypotension, repeated episodes of kidney and other organ ischemia may occur during RRT. Hypotension during RRT is often triggered by fluid removal. At the same time, there is some evidence that more aggressive ultrafiltration could be beneficial in AKI-RRT. Albumin is a protein that is the primary contributor to the colloid oncotic pressure maintaining the effective circulating volume (ECV) during RRT. Critically ill patients with AKI-RRT are nearly always hypoalbuminemic. Despite its high cost and limited evidence to support the practice, intravenous hyperoncotic albumin is commonly administered to patients with AKI-RRT in an effort to boost the colloid oncotic pressure and maintain the blood pressure while simultaneously facilitating fluid removal Objective: This proposed trial is intended to provide definitive evidence as to the efficacy of a frequently used and expensive intervention to promote hemodynamic stability and augment ultrafiltration during RRT in critically ill patients Design: A randomized controlled trial with two parallel arms. Setting: The mixed medical-surgical intensive care units of five Canadian tertiary care hospitals with plans to expand to include other centres across Canada and internationally. Study Population: 856 patients admitted to the Intensive Care Unit (ICU) with AKI requiring treatment with RRT . Intervention: Participants will be randomized 1:1 to receive either albumin (20-25%) boluses or normal saline placebo boluses at the start and halfway through RRT sessions in ICU, during their RRT treatments to a maximum of 14 days.

Official Title
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Albumin To Enhance Recovery After Acute Kidney Injury: A Multi-Centre, Randomized, Controlled Trial

Conditions
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Acute Kidney Injury, Renal Replacement Therapy, Hypotension, Critical Illness

Intervention / Treatment
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* Biological: 20-25% Albumin fluid (100 mL)
* Other: 0.9% Normal Saline (100 mL)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old; Admission to a critical care unit/intensive care unit (ICU) for > 24 hours; Receiving vasoactive therapy AND/OR undergoing mechanical ventilation (including non-invasive mechanical ventilation (NIMV)); Immediate initiation of RRT for management of AKI is planned OR additional RRT sessions are imminently planned for patients who already received RRT during their ICU admission; Exclusion Criteria: Initiation of RRT for reasons other than AKI (e.g. drug intoxication, hypothermia) ; Known pre-hospitalization end-stage kidney disease; Kidney transplant within the past 365 days; Presence or clinical suspicion of renal obstruction, rapidly progressive glomerulonephritis, vasculitis, thrombotic microangiopathy or acute interstitial nephritis; Advanced cirrhosis (Child Pugh class C [score 10-15]), spontaneous bacterial peritonitis or hepatorenal syndrome; Acute peritoneal dialysis used as the initial RRT modality; Contraindications to albumin: Admitted with traumatic brain injury Increased intra-cranial pressure in those with intra-cranial pressure monitoring Prior history of anaphylaxis to intravenous albumin Contraindication or known objection to albumin/blood product transfusions Already received 2 or more RRT sessions during ICU admission. Limitations of medical therapy precluding RRT/mechanical ventilation/vasoactive medications or plan to transition to palliation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized controlled trial with two parallel arms 1:1
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 20-25% Albumin fluid<br>100 mL 20-25% Albumin fluid at the initiation of continuous renal replacement therapy (CRRT), prolonged intermittent renal replacement therapy (PIRRT), or intermittent hemodialysis (IHD) and another 100 mL 20-25% Albumin fluid and halfway through RRT sessions in ICU. | Biological: 20-25% Albumin fluid (100 mL)<br>* Participants will be randomized to receive albumin (20-25%) during their RRT sessions (either CRRT, SLED or IHD) in ICU. Once randomized the same fluid will be given for all subsequent RRT sessions for up to 14 days in ICU. RRT sessions will be determined as per the treating physician. Boluses will be given at the start of, and halfway through, RRT sessions (i.e. for SLED sessions, at 0 and 4 hours; for IHD sessions, at 0 and 2 hours).<br>|
| Placebo Comparator: Normal Saline<br>100 mL at the initiation of CRRT, SLED or IHD and another 100 mL 0.9% Normal Saline halfway through RRT sessions in ICU. | Other: 0.9% Normal Saline (100 mL)<br>* Participants will be randomized to receive normal saline 100 mL boluses during their RRT sessions (either CRRT, SLED or IHD) in ICU. Once randomized the same fluid will be given for all subsequent RRT sessions for up to 14 days in ICU. RRT sessions will be determined as per the treating physician. Boluses will be given at the start of, and halfway through, RRT sessions (e.g. for 8 hour SLED sessions, at 0 and 4 hours; for 4 hour IHD sessions, at 0 and 2 hours; for CRRT, after starting/randomization then every 12 hours while continuing on CRRT).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Organ-support-free days (OSFD) | Organ support-free days are defined as days that are both: 1) vasoactive therapy-free; AND 2) mechanical ventilation-free (including NIMV). For patients who die within 28 days following randomization, organ support-free days are counted as -1. An OSFD will be defined as the receipt of < 2 hours of any vasoactive therapy provided by continuous infusion AND the receipt of < 2 hours of either invasive or non-invasive mechanical ventilation, within a 24-hour period. | 28 days following randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RRT-free days through day 28 | For each patient, one point will be given for each calendar day that a patient was free of RRT. For patients who die within 28 days following randomization, RRT-free days are counted as -1. An RRT-free day will be defined as a 24-period in which < 2hours of CRRT was received within a 24-hour period and no intermittent RRT sessions were started during the 24-hour period. | Through day 28 | 
| Vasoactive therapy free days | For patients who die within 28 days following initiation of randomization, vasoactive therapy-free days are counted as -1. Vasoactive therapy-free days will be defined as receipt of < 2 hours of any vasoactive therapy provided by continuous infusion within a 24-hour period | Through day 28 | 
| Mechanical ventilation-free days | For patients who die within 28 days following initiation of randomization, mechanical ventilation-free days are counted as -1. Mechanical ventilation-free days will be defined as receipt of < 2 hours of either invasive or non-invasive ventilation during a 24-hour period. Invasive mechanical ventilation is that provided via endotracheal tube (including tracheostomy). Noninvasive ventilation will be counted when more than 5 cm H2O of continuous positive airway pressure and more than 5 cm H2O of pressure support when deployed to avoid intubation. Other uses of noninvasive ventilation (eg, chronic nighttime use for chronic obstructive pulmonary disease) will not be counted. | Though day 28. | 
| ICU free days | For patients who die within 28 days following initiation of randomization, ICU-free days are counted as being -1. ICU-free days will be defined as admission to an ICU for < 2 hours within a 24-hour period | Through 28 days | 
| Number of participants with death in ICU | Mortality within 28 days since randomization | Through 28 days | 
| Number of participants with all-cause mortality at 28 days | Mortality within 28 days since randomization | Through 28 days | 
| Number of participants with all-cause mortality at 90 days | Mortality within 90 days since randomization. | Through 90 days. | 
| Number of participants with death in ICU, at 28 days, and in-hospital | Days from randomization to death in ICU, at 28 days or in-hospital | Through 90 days | 
| Number of participants with RRT dependence at 90 days among surviving patients | Defined by the receipt of any form of RRT within +/- 14 days of the 90-day time point following randomization for those alive at 90-days following randomization | Through 90 days. | 
| Number of participants with composite of death or RRT dependence at 90 days | Defined as death within 90-days following randomization or the receipt of any form of RRT within +/- 14 days of the 90-day time point following randomization | Through 90 days. | 
| eGFR will be evaluated in all patients alive at Day 90 | Serum creatinine will be drawn at day 90 (or as close as possible to day 90) and not beyond 132 days after randomization (i.e. we will accept a serum creatinine from Day 90 minus 14 days to Day 90 plus 42 days). eGFR will be derived from the CKD-EPI Creatinine (2021) equation that excludes the race-based coefficient and expressed in mL/min/1.73 m2 | At 90 days | 
| Major adverse kidney outcomes, defined as death, RRT dependence, or sustained reduction in kidney function (defined as eGFR < 75% baseline eGFR) at 90 days. | eGFR will be derived from the CKD-EPI Creatinine (2021) equation that excludes the race-based coefficient69 and expressed in mL/min/1.73 m2 | Through 90 days | 
| Hospitalization-free days | Defined as a 24-hour period completely free of an inpatient hospitalization. | Through 90 days. | 
| EuroQoL EQ-5D-5L which includes a descriptive system (scored from 5 (worst) to 25 (best)) and a visual analogue scale (scored from 0 (worst) to 100 (best)) at day 90. | Survivors at 90 days will be contacted and evaluated using the EQ-5D-5L which is a measure of health-related quality of life and patient utility | At 90 days | 
| Occurrence of RRT-associated hypotension (for every RRT session in ICU after randomization) | Defined as: a drop in blood pressure during RRT requiring initiation or increase in dose of a vasopressor during RRT session or premature discontinuation of RRT session due to hypotension | Through 14 days | 
| Daily fluid balance after randomization up until ICU discharge or day 14, whichever comes first | Daily net fluid will be calculated based on the medical chart | Day 14 or ICU discharge | 
| Difference between ordered and achieved ultrafiltration for all intermittent HD / SLED treatments will be determined according to the medical record up until ICU discharge or day 14, whichever comes first | volume will be determined according to the medical record | Day 14 or ICU discharge | 
| Daily Sequential Organ Failure Assessment score (SOFA) score after enrollment up until ICU discharge or day 14, whichever comes first | The renal component of the SOFA score will be calculated on the basis of urine output only (as all participants will receive RRT and this impacts the creatinine value). The GCS score will not be used for the total score (GCS score is difficult is accurately determine in an intubated and sedated participant) | Day 14 or ICU discharge | 
| Health Care Costs | An economic evaluation will include the cost of the intervention and control will be assessed using a micro-costing approach,1plus any implications on length of stay, safety events associated with the intervention and/or control, and the costs associated with RRT-dependence up to 365 days following randomizationTo measure these impacts, we will assess hospital and ICU use, physician claims, and subsequent outpatient claims for RRT for all patients within the trial. Consistent with usual practice within a multi-centre clinical trial, valuation of costs will be done for the subset of all patients enrolled within the province of Ontario, Canada (extrapolated based on all patients in the trial) using administrative costing data available from the Institute for Clinical Evaluative Sciences (IC/ES). | Through 365 days. | 
| Number of alive participants with RRT-dependence at 365 days | defined by the patient having a kidney transplant or receipt of any form of RRT within 14 days before or after the 365-days post-randomization time-point | Through 365 days | 
| Number of participants with all-cause mortality at 365 days | Mortality within 365 days since randomization. | Through 365 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Albumin, Normal Saline, Dialysis, Intensive Care Unit