STandard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI): A Multi-Centre, Randomized, Controlled Trial (Principal Trial)
Phase: NA
Conditions: Acute Kidney Injury
Sponsor: Unity Health Toronto

 
STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney 
Injury (STARRT-AKI): A Multi-Centre, Randomized, Controlled Trial  
 
 
 
 
 
Protocol Version 
October 05, 2015  
CONFIDENTIAL 
 
 
 
Principal Investigators: 
 
Sean M. Bagshaw, MD MSc FRCPC 
Division of Critical Care Medicine, Faculty of Medicine and Dentistry 
University of Alberta 
Associate Professor, Division of Critical Care Medicine 
University of Alberta 
2-124E Clinical Sciences Building 
8440-112 Street 
Edmonton, Alberta 
T6G 2B7 
Phone: 780-492-3817 
Fax: 780-492-1500 
Email: bagshaw@ualberta.ca 
 
 
Ron Wald, MDCM MPH FRCPC 
Division of Nephrology, Department of Medicine 
St. Michael’s Hospital 
Assistant Professor, Department of Medicine 
University of Toronto 
30 Bond Street 
Toronto, Ontario 
M5B 1W8 
Phone: 416-867-3703 
Fax: 416-867-3709 
Email: waldr@smh.ca 
 
 
 
ClinicalTrials.gov Identifier: NCT02568722 
 
 

 
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Table of Contents 
Protocol Synopsis .................................................................................................................................. 4 
SECTION 1. BACKGROUND ................................................................................................................ 7 
1.1 Scope of the clinical problem ........................................................................................................ 7 
1.2 Study objectives ........................................................................................................................... 8 
1.3 Consensus regarding the need for a trial ...................................................................................... 8 
1.4 Review of the literature on the timing of RRT initiation in AKI ....................................................... 8 
1.5 Background work by the investigators .......................................................................................... 9 
1.5.1 National survey of current practice ......................................................................................... 9 
1.5.2 Cohort studies ........................................................................................................................ 9 
1.5.3 Systematic review on the timing of RRT initiation in AKI ...................................................... 10 
1.5.4 Completion of the STARRT-AKI pilot trial confirming the feasibility and safety of the protocol
 ..................................................................................................................................................... 10 
SECTION 2. TRIAL METHODOLOGY ................................................................................................. 11 
2.1 Trial design ................................................................................................................................. 11 
2.2 Eligibility criteria.......................................................................................................................... 11 
2.2.1 Screening overview .............................................................................................................. 11 
2.2.2 Inclusion criteria ................................................................................................................... 13 
2.2.3 Exclusion criteria .................................................................................................................. 14 
2.3 Trial intervention ......................................................................................................................... 17 
2.3.1 Allocation of participants ...................................................................................................... 17 
2.3.2 Accelerated RRT initiation (experimental arm) ..................................................................... 17 
2.3.3 Standard RRT initiation (control arm) ................................................................................... 17 
2.3.4 RRT delivery in the STARRT-AKI Trial ................................................................................. 18 
2.3.5 Criteria for discontinuation of renal replacement therapy...................................................... 18 
2.4 Frequency and duration of follow-up ........................................................................................... 18 
2.5 Outcomes ................................................................................................................................... 19 
2.5.1 Primary outcome .................................................................................................................. 19 
2.5.2 Secondary outcomes ........................................................................................................... 19 
2.5.3 Safety events ....................................................................................................................... 19 
2.5.4  Safety events potentially related to the central venous catheter (CVC) used for RRT ......... 20 
2.6 Safety outcomes......................................................................................................................... 21 
2.6.1 Definition of a serious adverse event ................................................................................... 21 
2.7 Measurement of outcomes ......................................................................................................... 22 
2.7.1 Primary outcome .................................................................................................................. 22 
2.7.2 Secondary outcomes ........................................................................................................... 22 
2.8 Health resource utilization analysis............................................................................................. 23 
2.9 Sample size justification ............................................................................................................. 23 

 
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2.10 Analysis plan ............................................................................................................................ 24 
2.11 Planned recruitment rate and methods to ensure enrollment .................................................... 24 
2.12 Co-Enrollment .......................................................................................................................... 25 
2.13 Study centres ........................................................................................................................... 25 
2.14 Mitigation of bias ...................................................................................................................... 25 
SECTION  3. TRIAL MANAGEMENT .................................................................................................. 26 
3.1 The Coordinating Centre ............................................................................................................ 26 
3.2 Role of the site investigators ...................................................................................................... 27 
3.3 Role of the local study coordinators ............................................................................................ 27 
3.4 Steering Committee .................................................................................................................... 27 
3.5 Data safety and monitoring board ............................................................................................... 27 
3.6 Sub-studies ................................................................................................................................ 28 
3.7 Ethics and consent issues .......................................................................................................... 28 
3.8 Publication and authorship policy ............................................................................................... 28 
REFERENCES .................................................................................................................................... 30 
 
 
 
 
 
 
 
 

 
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Protocol Synopsis 
Background: Acute kidney injury (AKI) is a common and devastating complication of critical 
illness. Once AKI is established, treatment is largely supportive and no intervention has been 
found to restore kidney function or improve overall survival. Renal replacement therapy (RRT), 
usually in the form of hemodialysis, is frequently needed to manage patients with severe AKI. 
Such patients have an in-hospital mortality that consistently exceeds 50% with delays in RRT 
initiation implicated as a possible contributor. A recent meta-analysis suggested that earlier 
initiation of RRT may improve survival, but this is based on data derived overwhelmingly from 
observational studies. Our group recently completed a multi-centre pilot randomized controlled 
trial that confirmed the feasibility of allocating patients to two different strategies of RRT 
initiation. Patient recruitment and follow-up, as well as patient safety, were successfully 
demonstrated during the pilot phase of this research program. 
 
Objectives: The objectives of this trial are to determine whether, in critically ill patients with 
severe AKI, randomization to accelerated initiation of RRT, compared to a conservative 
strategy consistent with standard care, leads to:  
1. Improved survival (primary outcome) at 90 days; and  
2. Recovery of kidney function (principal secondary outcome), defined as independence from 
RRT at 90 days 
 
Study Population: We will enroll 2,866 critically ill patients with severe AKI who do not have 
an urgent indication for RRT initiation at the time of screening but who have a reasonable 
likelihood of ultimately requiring RRT. Recruitment will occur at centres in Canada, the USA, 
Australia, New Zealand, the UK, Austria, and potentially several other countries. 
 
Inclusion criteria (all need to be fulfilled for eligibility):  
1- Age ≥ 18 years 
 
2- Admission to an critical care unit (CCU) 
 
3- Evidence of kidney dysfunction [serum creatinine ≥100 µmol/L (women) and ≥ 130 µmol/L 
(men)] 
 
4- Evidence of severe AKI defined by at least 1 of the following 3 criteria:  
       i) ≥ 2-fold increase in serum creatinine from a known pre-morbid baseline or during the 
current hospitalization; OR  
       ii) Achievement of a serum creatinine ≥ 354 µmol/L with evidence of a minimum 
increase of 27 µmol/L from pre-morbid baseline or during the current hospitalization; 
OR 
       iii) Urine output < 6.0 mL/kg over the preceding 12 hours  
 
 
Exclusion criteria (any of the following factors will result in ineligibility): 
1- Serum potassium > 5.5 mmol/L 
 
2- Serum bicarbonate < 15 mmol/L 
 

 
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3- Presence of a drug overdose that necessitates initiation of RRT 
 
4- Lack of commitment to ongoing life support (including RRT) 
 
5- Any RRT within the previous 2 months (either acute or chronic RRT) 
 
6- Kidney transplant within the past 365 days 
 
7- Known pre-hospitalization advanced chronic kidney disease, defined by an estimated 
glomerular filtration rate < 20 mL/min/1.73 m2  
 
8- Presence or clinical suspicion of renal obstruction, rapidly progressive glomerulonephritis, 
vasculitis, thrombotic microangiopathy or acute interstitial nephritis 
 
9- Clinician(s) caring for patient believe(s) that immediate RRT is absolutely mandated 
 
10- Clinician(s) caring for patient believe(s) that deferral of RRT initiation is mandated 
 
The patient or substitute decision maker will be asked to provide consent within 12 hours of 
the above criteria being met. Alternatively, in the absence of a substitute decision maker and 
where approved by the local Ethics Board, enrollment by deferred/delayed consent will need to 
be documented within 12 hours of the above criteria being met. The patient will be excluded if 
consent cannot be obtained (or enrollment by deferred/delayed consent cannot be 
documented) during this time window. 
 
Interventions 
Accelerated RRT initiation (experimental arm): A dialysis catheter will be placed and RRT 
initiated as soon as possible and no more than 12 hours after the patient became fully eligible. 
 
Standard RRT initiation (control arm): In the absence of kidney function recovery, the 
initiation of RRT will be permitted if one of the following develops: serum potassium ≥ 6.0 
mmol/L; pH ≤ 7.20 or serum bicarbonate ≤ 12 mmol/L; evidence of severe respiratory failure, 
based on a PaO2/FiO2 ≤ 200 and clinical perception of volume overload; and/or persistent AKI 
> 72 hours following the time of randomization. Once a decision is made to start RRT, a 
dialysis catheter will be placed and RRT initiated as soon as possible. 
 
All aspects of RRT (i.e. RRT modality, dose, anticoagulation) administered to patients in both 
treatment arms will follow guidelines that reflect local practice and usual standards of care. 
 
Outcomes 
Primary outcome:  
All-cause mortality at 90 days. 
 
Secondary outcomes: 
1 - RRT dependence at 90 days among surviving patients. 
2 - Composite of death or RRT dependence at 90 days. 
3 - Estimated glomerular filtration rate among patients alive at Day 90. 
4 - Albuminuria at Day 90. 

 
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5 - Major adverse kidney outcomes, defined as death, RRT dependence or sustained 
reduction in kidney function (defined as eGFR < 75% baseline eGFR) at 90 days. 
6 - Mechanical ventilation-free days through day 28. 
7 - Vasoactive therapy-free days through day 28. 
8 - ICU-free days through day 28. 
9 - Hospitalization-free days through day 90. 
10 - Death in ICU, at 28 days, and in-hospital. 
11 - EuroQoL EQ-5D-5L (a measure of health-related quality of life and patient utility) at day 90 
and at 1 year among survivors. 
12 - Health care costs through day 365. 
13 – Vital status and RRT dependence at 365 days among survivors. 
 
Implications: 
The optimal timing of RRT initiation is an existing knowledge gap and a clear priority for 
investigation. With the successful completion of the STARRT-AKI pilot trial, the feasibility and 
relevance of the proposed interventions has been established. It is now time to definitively 
evaluate whether earlier/pre-emptive/accelerated RRT initiation is associated with enhanced 
survival as compared to a conservative strategy for initiation of RRT, which is driven by 
conventional indications and clinician judgment. 
 

 
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SECTION 1. BACKGROUND 
 
1.1 Scope of the clinical problem 
In critically ill patients who require support in an intensive care unit (ICU) setting, the 
development of acute kidney injury (AKI) is common. Recent epidemiologic data show that AKI 
rates among critically ill patients are increasing and that AKI complicates the ICU course in up 
to 67% of patients.1-4 For critically ill patients with more severe forms of AKI, renal replacement 
therapy (RRT), also known as dialysis, is frequently employed.5 For these individuals, RRT 
initiation often results in a considerable escalation in both the complexity and associated costs 
of care.6 Moreover, these critically ill patients experience substantial morbidity, including non-
recovery of kidney function and RRT dependence,7-9 and excess mortality, with hospital case-
fatality rates commonly exceeding 50%.5,10 
 
Many aspects of RRT delivery to critically ill patients with AKI remain uncertain resulting in 
heterogeneity in the prescription and delivery of acute RRT.11,12 Life threatening scenarios 
such as severe hyperkalemia, profound non-lactate-related metabolic acidosis, and severe 
fluid overload resulting in respiratory failure are complications of AKI that can be readily 
corrected with RRT. In such situations, the need to initiate RRT is unequivocal. However, in 
the ICU, patients with severe compromise of kidney function without these complications are 
commonly encountered. The optimal time for initiating RRT in patients without a life-
threatening complication of AKI is unknown. 
 
Initiating RRT earlier in critically ill patients with AKI may confer better control of uremia, acid-
base homeostasis, electrolyte imbalances, extracellular volume accumulation and systemic 
inflammation. The earlier initiation of RRT would also prevent the development of a life-
threatening complication of AKI such as a hyperkalemia-associated arrhythmia. Intuitively, the 
earlier initiation of RRT in the absence of life-threatening complications may confer a variety of 
benefits and is supported by the preponderance of available data, mostly derived from 
observational studies.13,14 As a result, this practice has become common and endorsed by key 
opinion leaders. On the other hand, there is no high quality evidence to support the notion that 
the initiation of RRT - in the absence of a life-threatening complication of AKI – modifies 
clinically important outcomes. This problem is compounded by the fact that RRT is associated 
with potential risks and entails significant costs.16 Furthermore, most of the observational 
studies did not consider patients with AKI who did not receive RRT. There is a possibility that 
with a strategy of supportive management and the introduction of RRT only when a life-
threatening complication supervenes, some patients with severe AKI might recover kidney 
function spontaneously without ever starting RRT. As a result, widespread adoption of a 
clinical strategy of early RRT commencement might expose patients, some needlessly, to the 
risks of RRT while inflating costs.  
 
As a consequence, there is a critical knowledge gap in evidence to guide the ideal 
timing and circumstances for initiation of RRT in critically ill patients with AKI. The 
Acute Kidney Injury Network (AKIN), an international working group comprised of experts from 
both nephrology and critical care, identified the question, “When should RRT be initiated, 
and does timing affect outcome?” as the highest-ranked priority research topic by both 
nephrologists and critical care experts.17 Noting the absence of evidence in this area, the 
recently-released Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice 

 
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Guideline for AKI recommended the pursuit of research to “Determine [if] early vs late start 
of RRT….results in improved outcomes (eg, mortality, evolution to chronic kidney 
disease stage 5) in AKI patients.”18 The National Institute for Health and Care Excellence 
(NICE) in the United Kingdom recently issued a statement, as part of its set of Guidelines on 
AKI noting that “A prospective study is needed of adult inpatients with acute kidney 
injury AKIN stages 2 and 3, who are likely to need renal replacement therapy within a 
given timeframe (for example, 72 hours), but have no urgent need for therapy.”19 This is 
in essence the trial we have planned. In summary, there is international consensus around the 
necessity to perform a definitive trial to determine whether the earlier initiation of RRT leads to 
improved patient-relevant outcomes. A trial showing superior survival with accelerated RRT 
initiation will establish this approach as the standard of care; on the other hand, the absence of 
superiority of an accelerated RRT strategy will justify a more conservative approach to RRT 
initiation thereby leading to significant resource savings. As a result, our proposed trial will 
have a meaningful clinical impact irrespective of its findings. 
 
1.2 Study objectives 
The principal research questions for the proposed trial are:  
In critically ill patients whose course is complicated by the development of AKI, and who do 
NOT have urgent clinical indications to commence RRT, does the accelerated initiation of 
RRT, compared with initiation of RRT using standard indications and clinical judgment, lead to  
1) A lower risk of mortality at 90 days (primary outcome)? 
2) A lower likelihood of persistent RRT dependence at 90 days among survivors 
(principal secondary outcome)? 
This proposed trial is intended to be the definitive guide for clinical practice and address one of 
the most pressing and controversial questions in the field of Critical Care Nephrology. 
 
1.3 Consensus regarding the need for a trial 
The acute delivery of RRT to critically ill patients with AKI is common practice; yet there have 
been controversies regarding the optimal delivery of RRT for these patients that have been 
clarified in recently completed randomized trials. These have largely focused on the delivered 
dose/intensity of RRT,20-22 RRT modality23,24 and RRT clearance mode.25,26 However, 
characterization of the optimal time to initiate RRT, in particular whether earlier 
initiation translates into improved clinical outcomes, remains unknown, and is a clear 
priority for higher quality evidence. 18 
 
1.4 Review of the literature on the timing of RRT initiation in AKI 
A number of retrospective cohort studies have suggested that earlier RRT initiation may 
improve outcomes. Gettings et al performed a retrospective single centre study of trauma-
related AKI where a serum urea of 21.4 mmol/L at RRT initiation was used as a cut-off to 
discriminate between early and late RRT.27 This study found that “early RRT” was initiated 
nine days earlier than “late RRT”, and was associated with a shorter total hospitalization and 
lower mortality (61% for “early” starters vs 80% for “late” starters). In a multicentre 
retrospective cohort study, Liu et al found that “early RRT” (initiation when serum urea 
concentration was < 27.1 mmol/L) was associated with a lower adjusted-risk of death.28 These 
studies are at odds with another multicentre observational study of timing of RRT in critically ill 
patients which found no significant difference in the adjusted odds for mortality when lower 
serum urea concentration was used as a surrogate for earlier RRT initiation.29 

 
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Bouman et al randomized 106 predominantly post-cardiac surgical patients with AKI at a 
single-centre to early (soon after meeting criteria for AKI) or late (following development of a 
classic indication for RRT) RRT initiation.30 They found no difference in mortality; however, the 
trial was underpowered, and may not be generalizable due to unexpectedly high survival and 
the preponderance of cardiac surgery-associated AKI. A recently published trial of 208 patients 
with community-acquired AKI was conducted at a single-centre in India.31 In the earlier RRT 
arm, RRT commenced once urea exceeded 25 mmol/L or serum creatinine exceeded 619 
µmol/L irrespective of other AKI complications. In the usual-start arm, RRT was only initiated in 
the setting of medically-refractory hyperkalemia, acidosis or volume overload or in the setting 
of uremic symptoms. No difference in mortality or kidney recovery was observed. Applicability 
of these findings remains limited due to the young age of the patients (mean 42 y), the 
spectrum of illnesses associated with AKI (> 50% tropical infections or obstetric complications) 
and the fact that most patients were not critically ill. Moreover, the trial was inadequately 
powered to detect a realistic treatment effect for earlier RRT. In summary, the available 
evidence suggests that there may be clinical benefit to earlier RRT initiation in critically ill 
patients with AKI; however, clear inferences are limited by the small size of the completed 
trials, variable definitions for study inclusion and limited generalizability to a broad spectrum of 
ICU patients.  
 
1.5 Background work by the investigators 
The current proposal is the culmination of a multi-pronged research program led by the 
investigative team. 
 
1.5.1 National survey of current practice 
We performed a survey of Canadian nephrologists and intensive care clinicians to better 
understand their attitudes and behaviors regarding the timing of RRT initiation in patients with 
AKI. The survey was distributed to members of the Canadian Society of Nephrology and the 
Canadian Critical Care Society. We asked respondents whether they would consider it ethical 
to conduct a randomized trial of RRT timing in critically ill patients with AKI where patients 
would be randomized to either “early” or “standard-of-care” initiation of RRT. Amongst 
respondents, 94% believed it would be ethical to randomize patients in such a trial, strongly 
suggesting there is equipoise among Canadian intensivists and nephrologists regarding the 
issue of timing of RRT initiation.32 Our findings have been confirmed in two further surveys 
conducted in the United States and Europe.33,34 
 
1.5.2 Cohort studies 
In a secondary analysis of the multinational Beginning and Ending Supportive Therapy (BEST) 
for the Kidney study, we evaluated the timing of initiation of RRT in 1238 critically ill patients 
with AKI.29 Timing of RRT was stratified into “early” and “late” using several markers: serum 
urea (< and ≥ 24.2 mmol/L, respectively), serum creatinine (< and ≥ 309 µmol/L, respectively), 
urine output, and time from ICU admission to start of RRT. In a multivariate analysis, after 
adjustment for demographics, baseline kidney function, illness severity, primary diagnosis, and 
contributing factors for AKI, there was no association between serum urea concentration at 
RRT initiation and hospital mortality (OR, 1.25; 95% CI, 0.91-1.70; p=0.16). While higher 
serum creatinine concentration at the time of RRT initiation was associated with significantly 
lower adjusted-mortality (OR, 0.51; 95% CI, 0.37-0.69; p=0.001), late RRT defined relative to 
time from ICU admission (≥ 5 days) was associated with higher adjusted-mortality (OR, 1.95; 

 
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95% CI, 1.30-2.92; p=0.001). Furthermore, the duration of RRT, the likelihood of RRT 
dependence at hospital discharge, and hospital length-of-stay were greater when the interval 
from ICU admission to RRT initiation was prolonged. 
 
To characterize current Canadian practice, we performed a prospective cohort study to 
describe the characteristics of critically ill patients with AKI at the time of RRT initiation and 
their association with mortality at six intensive care units in Edmonton and Toronto (n=234).35 
At RRT initiation, median serum creatinine and urea were 331 μmol/L and 22.9 mmol/L, 
respectively. Oligo-anuria (urine output <400mL/24hr) was present in 32.9% and 92.2% had a 
positive fluid balance. Notably, only 16.2% had significant hyperkalemia (serum potassium ≥ 
5.5 mmol/L) and 33.8% had important metabolic acidosis (serum bicarbonate ≤ 15 mmol/L) at 
RRT initiation. We found several factors at the time of RRT initiation to be independently 
associated with hospital mortality including: creatinine < 332 μmol/L (odds ratio 2.8, 1.5-5.4), 
change in urea from ICU admission > 8.9 mmol/L (OR 1.8, 1.0-3.4), urine output <82 mL/24hr 
(OR 3.0, 1.4-6.5), fluid balance exceeding 3.0 L/24hr (OR 2.27, 1.2-4.5) on the day prior to 
RRT initiation, Sequential Organ Failure Assessment score36 >14 (OR 2.3, 1.3-4.3), and RRT 
initiation ≥4 days from ICU admission (OR 4.3, 1.9-9.5). While these data provide insight into 
the clinical, physiologic and laboratory parameters at the time RRT was initiated, there is no 
information on the factors clinicians used to decide when to initiate RRT. We performed an 
additional survey to clarify the triggers that clinicians used to start RRT in 119 critically ill 
patients with AKI from 11 centres across Canada.37 The most common factors influencing the 
decision to start RRT were oligoanuria (72%), metabolic acidosis (48%), azotemia (34%), and 
pulmonary edema (29%). These data confirmed that the decision to initiate RRT is often 
influenced by numerous clinical factors; 79% of patients had two or more triggers for initiation 
of RRT. These data provided key insights into the current standard-of-care for RRT initiation in 
Canada and have been complemented by observations from other parts of the world in order 
to inform the eligibility criteria for the STARRT-AKI program.38,39  
 
1.5.3 Systematic review on the timing of RRT initiation in AKI 
We have performed a systematic review and meta-analysis examining timing of RRT initiation 
in critically ill patients with AKI.13 We included controlled studies that specifically focused on 
adult critically ill patients with AKI receiving RRT where timing was evaluated and mortality 
was reported. We identified 15 unique studies for inclusion (2 randomized trials, 4 prospective 
cohort studies, and 9 retrospective cohort studies) published between 1999 and 2010. Overall 
study quality was generally low. In a pooled analysis, early initiation of RRT was associated 
with a significantly reduced odds of death (OR 0.45; 95% CI, 0.28-0.72) when compared to 
delayed or late RRT initiation amidst important heterogeneity (I2 = 78%). We believe that these 
findings, while limited in inference due to the observed heterogeneity, confirm equipoise for a 
prospective randomized trial evaluating whether accelerated/early initiation compared to a 
conservative strategy for RRT initiation in critically ill patients with AKI can impact patient 
survival and kidney recovery.  
 
1.5.4 Completion of the STARRT-AKI pilot trial confirming the feasibility and safety of 
the protocol 
We completed a CIHR-funded 12-centre RCT that confirmed the feasibility and safety of our 
protocol.40,41 We identified 132 individuals who met all the eligibility criteria and enrolled 101 
individuals (77%; pre-specified target > 50% for enrollment of eligible patients). The median 
time from eligibility to initiation of RRT was 7.4 hours in the accelerated arm and 3/48 (6%) 
participants commenced RRT beyond the specified 12-hour window for that treatment arm. In 

 
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the standard arm, 33/52 individuals (63%) commenced RRT, 6 (12%) died without the initiation 
of RRT while the remaining participants experienced recovery of kidney function and did not 
commence RRT. Among patients who did commence RRT, the median time from eligibility to 
RRT initiation was 31.6 hours. No participants in the standard arm commenced RRT within the 
first 12 hours of study eligibility. Overall, adherence to the study protocol exceeded the pre-
specified target of > 90% in each study arm. All patients were followed to Day 90 (pre-
specified target > 95%). A careful review of adverse events and severe adverse events did not 
reveal any tendency to harm in either study arm. An independent Data Safety Monitoring 
Board oversaw the trial and concluded that there were “…no study-related safety concerns 
that require report to the site Ethics/Institutional Review Boards or other regulatory authorities.” 
 
 
SECTION 2. TRIAL METHODOLOGY 
 
2.1 Trial design     
This multicentre, open-label, randomized controlled trial will compare an accelerated (or 
early/pre-emptive) approach to the initiation of RRT versus a conservative strategy of initiation 
of RRT as guided by standard indications and clinical judgment in critically ill patients with AKI. 
Two thousand eight hundred sixty six (2,866) critically ill patients with evidence of severe AKI 
will be randomized 1:1 to receive accelerated versus standard RRT initiation.  
 
2.2 Eligibility criteria 
 
2.2.1 Screening overview 
Research coordinators will screen the ICU population at each of the participating sites. 
Screening sweeps will occur in the morning and afternoon. Individuals with signs of AKI who 
are not initially eligible for the trial will be re-screened as several of the conditions for eligibility 
are dynamic. On a practical level, screening will begin by examination of the patient’s 
bloodwork. To meet preliminary eligibility criteria, sCr must exceed 100 µmol/L in women and 
130 µmol/L in men. The coordinator will only continue screening the patient record if this sCr 
threshold is exceeded. If the other inclusion criteria are met and NONE of the exclusion criteria 
are met, the patient will be considered provisionally eligible. Once provisionally eligible, the 
clinicians (Critical Care and/or Nephrology) caring for the patient will be asked if they believe 
that either the immediate initiation of RRT is mandated or the deferral of RRT is mandated. If 
the answer is negative to both these questions, the patient will be considered fully eligible and 
efforts to obtain consent will commence. If a patient’s eligibility is excluded by a clinician but 
RRT has not yet commenced at the subsequent screening round, the patient may be 
reconsidered for participation in the trial, and the clinician re-approached about the need to 
initiate/defer RRT, provided the patient still meets the other eligibility criteria. 
 
 
 

 
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A suggested approach to identifying eligible patients is found below: 
 

 
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In addition we will request, at sites where this is feasible, permission from Ethics Boards to 
collect a minimal data set (demographic data, some baseline lab values, receipt of RRT, and 
outcomes) on those patients who are provisionally or fully eligible at screening, but are 
excluded from participation due to one of: 
 
a. Clinician(s) belief that either immediate RRT OR deferral of RRT initiation is absolutely 
mandated (exclusion criteria 9 and 10) 
 
b. Inability to obtain consent within 12 hours of the patient meeting eligibility criteria  
 
The collection of this minimal data set will enable comparisons between patients in the above 
groups with patients who ultimately participate in order to ensure that there are no fundamental 
problems with the trial's generalizability.   
 
2.2.2 Inclusion criteria  
All of these must be fulfilled at the time of screening assessment: 
 
1- Age ≥ 18 years (Operational definition: Patient’s age on the day of eligibility screening.) 
 
2- Admission to a critical care unit (Operational definition: Any unit where there is capability to 
administer invasive mechanical ventilation.) 
 
3- Evidence of kidney dysfunction (Operational definition: serum creatinine ≥100 µmol/L 
[women] and  ≥ 130 µmol/L [men] based on most recent bloodwork available prior to 
screening and that has not declined by > 27 µmol/L compared to the highest value recorded 
in the preceding 48 hours.) 
 
4- Evidence of severe AKI based on at least one of the following three criteria:  
 
i) 
≥ 2-fold increase in serum creatinine (sCr) from baseline (Operational definition: The 
baseline sCr is an outpatient reading within 365 days of the current admission date; if 
multiple pre-hospitalization values are available, the one closest to the date of 
hospital admission will be used.  If an outpatient pre-hospitalization value is not 
available during the 365 days prior to admission date, the lowest creatinine value 
obtained during the current hospitalization should be taken as the baseline. This 
criterion is met if the current sCr is ≥ 100% higher than the baseline value.) 
 
ii) 
If current serum creatinine is ≥ 354 µmol/L, this must be accompanied by evidence of 
a minimum increase of 27 µmol/L from the baseline sCr. (Operational definition: If 
current sCr is > 354 µmol/L and the patient has experienced an increase of 27 µmol/L 
from the documented baseline, based on the definition delineated in i) for baseline 
sCr.) 
 
iii) 
Urine output < 6.0 mL/kg over the preceding 12 hours.  
 
 

 
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2.2.2.1 Rationale for inclusion criteria 
The inclusion criteria are designed to identify a population of critically ill adults with severe AKI 
who have an increased likelihood of requiring RRT at some point during their hospitalization 
but who do NOT need immediate RRT at the time of eligibility assessment.  
 
Criterion 3, Evidence of kidney dysfunction: This criterion will be used as an initial screen to 
identify patients with some degree of kidney dysfunction in whom RRT may be considered if 
the remainder of the criteria are met. It provides a useful entry point for coordinators to screen 
patients quickly and only consider individuals further if there is an elevation in sCr. 
 
Criterion 4, Evidence of severe AKI: Determination of severe AKI will be grounded in the 
staging system outlined in the Kidney Disease Improving Global Outcomes (KDIGO) 
Guidelines for Acute Kidney injury.18 This classification system stages AKI into three levels 
based on the extent of sCr elevation in parallel with the degree and duration of oliguria; 
patients are classified based on the worst finding (either sCr or oliguria). In order to identify 
patients with severe AKI in whom RRT may be contemplated, patients must have evidence of 
at least Stage 2 AKI, which constitutes either a doubling of sCr or urine output < 0.5 mL/kg/hr x 
12 hours (adapted to < 6 mL/kg over preceding 12 hours for ease of screening) or if the sCr is 
above 354 µmol/L at the time of screening, evidence that the sCr rose by at least 27 µmol/L 
from baseline. 
 
2.2.3 Exclusion criteria  
Any one of the criteria below would be grounds for exclusion: 
 
1- Serum potassium concentration  > 5.5 mmol/L (Operational definition: Based on last 
available bloodwork). 
       
2- Serum bicarbonate concentration < 15 mmol/L (Operational definition: Based on last 
available bloodwork). 
       
3- Presence of a drug overdose that necessitates initiation of RRT. (Operational definition:  If 
noted in the chart or directly from the treating team as the primary reason for administering 
RRT.) 
 
4- Lack of commitment to provide RRT as part of limitation of ongoing life support. 
(Operational definition: Critical care team has deemed the patient not to be eligible for 
escalation of life support, including the initiation of RRT, or substitute decision makers have 
declined offer of same.) 
 
5- Any RRT within the previous 2 months. (Operational definition: If recorded in the medical 
chart by any clinician following the patient.) 
 
6- Kidney transplant within the past 365 days. (Operational definition: As reflected in the 
medical chart.) 
 
7- Known pre-hospitalization advanced chronic kidney disease, defined by an estimated 
glomerular filtration rate < 20 mL/min/1.73 m2 in a patient who is not on chronic RRT. 
(Operational definition: The coordinator will review all documented serum creatinine values 

 
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within 365 days prior to the date of admission for the current hospitalization. The value 
closest to the admission date will be considered as the “baseline” and will be used to 
calculate the corresponding estimated glomerular filtration rate using an online calculator. A 
value of < 20 mL/min/1.73 m2 derived from the CKD-EPI equation42 will be grounds for 
exclusion. The serum creatinine, age, sex, and race (Black/non-Black) is entered into a 
calculator found at: http://www.qxmd.com/calculate-online/nephrology/ckd-epi-egfr. It is 
expected that a large number of patients will not have readily available pre-hospitalization 
sCr data. In the case of a missing pre-hospitalization sCr, this exclusion criterion will be 
considered to have been NOT met.) 
 
8- Presence or strong clinical suspicion of renal obstruction, rapidly progressive 
glomerulonephritis, vasculitis, thrombotic microangiopathy (eg, thrombotic thrombocytopenic 
purpura, hemolytic uremic syndrome, malignant hypertension, scleroderma renal crisis) or 
acute interstitial nephritis. (Operational definition: If explicitly described in the medical chart 
or strongly suspected as the cause of AKI by the clinicians following the patient.) 
 
IF THE PATIENT MEETS ALL OF THE ABOVE INCLUSION CRITERIA AND NONE OF 
EXCLUSIONS 1-8, THEN THE PATIENT IS DEEMED PROVISIONALLY ELIGIBLE AND 
THE ATTENDING CLINICIANS WILL BE APPROACHED BY THE RESEARCH TEAM TO 
CONFIRM THEIR COMFORT WITH THE TRIAL ENROLLMENT USING THE TWO 
EXCLUSION CRITERIA DESCRIBED BELOW 
 
9- Clinician(s) caring for patient believe(s) that immediate renal replacement therapy is 
absolutely mandated. (Operational definition: The study team will speak to the Critical Care 
attending physician, and at relevant sites, the Nephrology attending physician caring for the 
patient and ask if he/she agrees with the statement: “Renal replacement therapy must be 
initiated immediately in this patient.” If at least one of the clinicians answers “Yes”, the 
clinician will be asked to identify the primary reason for mandating the immediate start of 
RRT.) 
 
10- Clinician(s) caring for patient believe(s) that deferral of renal replacement therapy initiation 
is mandated. (Operational definition: The study team will speak to the Critical Care and, at 
relevant sites, the Nephrology attending physician caring for the patient and ask if he/she 
agrees with the statement:  “Renal replacement therapy must be deferred in this patient.” If 
at least one of the clinicians answers “Yes”, the clinician will be asked to identify the primary 
reason for mandating the delay in initiation of RRT.) 
 
2.2.3.1 Rationale for exclusion criteria  
Criterion 1: Hyperkalemia may predispose to dangerous cardiac arrhythmias. As a result, 
randomization of a patient with hyperkalemia to standard RRT initiation may be unethical. 
 
Criterion 2: Severe metabolic acidosis may impair normal cell functions and compromise 
sensitivity to vasopressor agents in patients who are hemodynamically unstable. As a result, 
randomization of a patient with significant metabolic acidosis to a strategy of standard RRT 
initiation may be unethical. 
 
Criterion 3:  It is not ethical to withhold RRT in the presence of a dialyzable toxin. 
 

 
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Criterion 4: Severe irreversible acute or chronic illness leading clinicians to curtail or not 
escalate care is grounds for exclusion as it is unlikely that the timing of RRT initiation will have 
an impact on clinical outcomes in these individuals. 
 
Criterion 5: The treatment effect of earlier RRT may be reduced by the receipt of any RRT in 
the preceding 2 months. 
 
Criterion 6: The risk of acute graft rejection is greatest within 1 year following transplant and 
this condition is addressed primarily with enhanced immunosuppression. 
 
Criterion 7: The prognosis of critically ill patients with severe chronic kidney disease may be 
disproportionately affected by chronic kidney disease rather than by the acute superimposed 
deterioration in kidney function (or any intervention for this deterioration) and such patients are 
routinely excluded from intervention trials in AKI.20 
 
Criterion 8: Since the prognosis of these conditions will largely be guided by ancillary therapies 
(e.g., relief of urinary obstruction, systemic immunosuppression), patients with AKI that is due 
to causes other than suspected acute tubular necrosis will be excluded.  
 
Criteria 9 and 10: Even after all the above eligibility criteria have been satisfied, it is crucial for 
the relevant attending clinician(s) to be comfortable with randomization to either group as this 
reflects clinical equipoise. 
 
Note regarding exclusions 9 and 10: Discussions with the attending physicians 
following the achievement of provisional eligibility are a crucial part of the enrollment 
process in this trial. Though patients may meet the study inclusion criteria and have 
none of exclusions 1-8, we are relying on clinician judgment to tell us whether a 
patient’s condition mandates immediate RRT initiation or alternatively, if a patient’s 
clinical condition is such that he/she is likely to have imminent kidney function 
recovery. Both such patients should be excluded from this trial. 
 
This approach understandably entails some degree of subjectivity on the part of the 
attending physicians. The trial will allow clinicians to utilize a variety of clinical tools to 
make their determination, as no single biomarker has emerged as an adequately robust 
predictor of AKI progression and the subsequent need for RRT. In patients with oliguric 
AKI, a patient’s response to a furosemide bolus is a frequently-employed prognostic 
tool of AKI progression in clinical practice; specifically, a limited response in terms of 
urine output (with varied definitions of what constitutes a “poor” response”) might 
suggest the patient is likely to require RRT or have AKI that will not recover in the near 
future. This diagnostic strategy, named the “Furosemide Stress Test” has been 
standardized and evaluated by Chawla and Koyner et al.43,44 In preliminary studies, they 
have found that a urine output of < 200 mL in the 2 hours that follow an intravenous 
furosemide bolus has strong sensitivity and specificity for AKI progression. Though not 
mandated by the trial, clinicians wishing to risk stratify prospective trial participants 
using this technique will be asked to follow the method outlined in the published 
studies (provided in the study Operations Manual). For example, for a provisionally 
eligible patient who clinicians are reluctant to enroll in STARRT-AKI due to the 
possibility of imminent renal recovery, a low urine output in response to a furosemide 

 
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bolus (ie, a “positive furosemide stress test”) might change the physician’s impression 
regarding trial eligibility. 
 
   
2.3 Trial intervention 
 
2.3.1 Allocation of participants 
Participants will be randomized 1:1 to accelerated vs standard initiation of RRT with variable 
block sizes and stratified by centre using a central randomization system that will be managed 
at the Applied Health Research Centre.  
 
2.3.2 Accelerated RRT initiation (experimental arm) 
A dialysis catheter will be placed and RRT initiated as soon as possible and within 12 hours of 
eligibility. This 12-hour window includes the time needed to obtain consent or, where 
permissible, to document enrollment by deferred/delayed consent. 
 
2.3.3 Standard RRT initiation (control arm) 
This treatment arm comprises a strategy of conservative management with respect to RRT 
initiation and RRT will only be initiated in the presence of the criteria below: 
 
a) Persistent severe AKI defined as sCr that remains > 50% of the value recorded at 
randomization 
 
AND at least one of the following indications for RRT initiation: 
 
a) Serum potassium ≥ 6.0 mmol/L, or 
b) pH ≤ 7.20 or serum bicarbonate ≤ 12 mmol/L, or  
c) Evidence of severe respiratory failure, based on a PaO2/FiO2 ≤ 200 and clinical perception 
of volume overload, or 
d) Persistent severe AKI (sCr remains > 50% the value recorded at randomization) for > 72 
hours from randomization 
 
Patients will be evaluated on a daily basis by research staff to ascertain the presence of 
indications for RRT and provide consistent reminders to clinicians about study-prescribed 
criteria for RRT initiation. Clinicians will be asked to not initiate RRT unless the above criteria 
are present. By the same token, the clinician is not obligated to commence RRT even if the 
above conditions are met. However, the experience from the pilot phase of this program 
showed that two-thirds of patients in the standard arm commenced RRT in the absence of 
meeting the above criteria highlighting the challenges of absolutely restricting the application of 
this therapy in the realities of clinical practice. Thus, RRT may still be commenced in the 
standard RRT initiation arm anytime at the discretion of the attending clinician(s) based on 
clinical judgment. The clinician will be asked to specify the primary reason for initiating RRT in 
the absence of meeting the trial-specified criteria. However, initiation of RRT within 12 hours of 
eligibility will be considered a protocol violation and the clinician will also be asked to provide 
the primary reason(s) for RRT commencement. The decision to initiate RRT in the standard 

 
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arm of the trial will have to be approved by the attending physician(s) involved in the 
patient’s care.  
 
 
Once a decision is made to start RRT, a dialysis catheter will be placed and RRT initiated as 
soon as possible. In the standard initiation group, it is expected that a proportion of participants 
may die before receiving RRT while others may experience recovery of kidney function thus 
obviating the need for RRT. 
 
2.3.4 RRT delivery in the STARRT-AKI Trial 
Other than the study intervention (i.e., differential timing of RRT initiation), all RRT delivered to 
patients in both treatment arms will follow an identical set of recommended guidelines that is 
compatible with contemporary clinical practice as described in the study Operations Manual. 
 
2.3.5 Criteria for discontinuation of renal replacement therapy 
Once started in either treatment arm, RRT will continue until one of the following 
circumstances is encountered:  
 
1- Death; or 
2- Withdrawal of life support in the context of a change in the goals of care; or  
3- Kidney function recovery with no need for continued RRT as per the nephrologist’s or critical 
care physician’s judgment. Guidance regarding the presence of renal recovery is found in 
the Operations Manual. RRT may be reinitiated at any time according to the same principles 
described in the Operations Manual.  
 
2.4 Frequency and duration of follow-up 
Each participant will be followed for up to 90 days following randomization, and where feasible, 
to one year from randomization using administrative data. 
 
Patients randomized to accelerated RRT initiation: After consent has been obtained from the 
patient or SDM (or enrollment by deferred/delayed consent documented), patients will be 
assessed frequently in order to ensure that the randomized intervention is correctly 
implemented (i.e., within 12 hours of eligibility). Study personnel will provide regular reminders 
to the clinical team until RRT is started. Even after 12 hours have elapsed, the study team will 
encourage the initiation of RRT as soon as possible. Reasons for delays will be recorded.  
 
Patients randomized to the standard RRT initiation strategy: Clinical and laboratory data will be 
reviewed daily for 14 days after randomization and clinicians will be notified if any indications 
have developed that prompt consideration of RRT initiation based on the criteria listed in 
Section 2.3.3. The initiation of RRT in a patient allocated to the standard arm must be 
approved by the attending physicians. 
 
Patients in both arms will receive identical daily follow-up from randomization until Day 14 for 
assessment of clinical and physiologic data. We will also monitor and collect data on all RRT 
that is administered during the first 14 days after randomization. Similarly, we will collect data 
on safety events  during this time period. Each participant will be followed to 90 days following 

 
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randomization and, where feasible, overall follow-up (using administrative databases and a 
phone call to ascertain quality of life) will conclude at 365 days following randomization.  
 
 
2.5 Outcomes 
2.5.1 Primary outcome 
The primary outcome will be all-cause mortality within 90 days of randomization. We chose this 
as our primary outcome as it is least susceptible to bias in an unblinded trial, is reliably 
captured and is of unquestionable clinical relevance. All-cause mortality has also been used as 
the primary outcome in all major trials involving RRT interventions in the ICU.20,21,23 
 
2.5.2 Secondary outcomes 
1 - RRT dependence at 90 days among surviving patients. 
2 - Composite of death or RRT dependence at 90 days. 
3 - Estimated glomerular filtration rate among patients alive at Day 90. 
4 - Albuminuria at Day 90. 
5 - Major adverse kidney outcomes, defined as death, RRT dependence or sustained 
reduction in kidney function (defined as eGFR < 75% baseline eGFR) at 90 days. 
6 - Mechanical ventilation-free days through day 28. 
7 - Vasoactive therapy-free days through day 28. 
8- ICU-free days through day 28. 
9 - Hospitalization-free days through day 90. 
10 - Death in ICU, at 28 days, and in-hospital. 
11 - EuroQoL EQ-5D-5L (a measure of health-related quality of life and patient utility) at day 90 
and at 1 year among survivors. 
12 - Health care costs through day 365. 
13 – Vital status and RRT dependence at 365 days among survivors. 
 
2.5.3 Safety events 
The following events related, all felt to be clinically significant consequences of the 
receipt of RRT, will be recorded through Day 14 (specific details on ascertainment of 
each event are found in the Operations Manual): 
 
1 - RRT-associated hypotension 
Defined as: A drop in blood pressure requiring one of:  initiation of a vasopressor during 
RRT session or need to escalate dose of a vasopressor during the RRT session or 
premature discontinuation of RRT session due to hypotension. 
 
2 - Severe hypophosphatemia 
Defined as: Serum phosphorus < 0.5 mmol/L on any bloodwork. 
 
3 - Severe hypokalemia  
Defined as: Serum potassium < 3.0 mmol/L on any bloodwork. 
 
4 - Severe hypocalcemia 

 
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Defined as: Albumin-adjusted serum calcium < 1.90 mmol/L or ionized calcium < 0.90 
mmol/L. 
 
5 - Allergic reaction  
Defined as: Clinician suspicion of allergic reaction to one of the components of the RRT 
apparatus. 
 
6 - Arrhythmia during RRT 
Defined as: New atrial (excluding sinus tachycardia or sinus arrhythmia) or ventricular 
arrhythmia that develops during RRT and was not present prior to initiation of RRT that 
requires treatment with any medication or cardioversion/defibrillation or decision to stop 
RRT prematurely as a result of arrhythmia. 
 
7 - Seizure  
Defined as: Seizure that develops during RRT session and confirmed by attending 
clinician. 
 
8 - Major Bleeding 
Defined as: 
a) Life threatening bleeding and associated hypovolemic shock (e.g., from ruptured 
abdominal aortic aneurysm or upper or lower gastrointestinal hemorrhage). 
b) Life threatening bleeding at a critical site (e.g., intracranial, retroperitoneal, pericardial). 
c) Overt, clinically important bleeding associated with one of the following within 24 hours of 
the bleed: decrease in hemoglobin >20 g/L or transfusion ≥ 2 packed red blood cells. 
d) Bleeding requiring an invasive intervention (e.g., re-operation). 
 
2.5.4  Safety events potentially related to the central venous catheter (CVC) used for 
RRT 
The following events related, all felt to be clinically significant consequences of the 
receipt of the CVC used for RRT, will be recorded through Day 14 (specific details on 
ascertainment of each event are found in the Operations Manual): 
 
1 - Hemorrhage at the site of CVC insertion  
Defined as: Bleeding described by clinician inserting catheter requiring transfusion of ≥ 1 
unit(s) of packed red blood cells and/or surgical intervention/repair within 12 hours following 
insertion. 
 
2 - CVC-associated bloodstream infection  
Defined as: Bloodstream infection in 2 blood culture sets (one drawn from dialysis catheter 
and the other from another site) with no proven alternative source for bloodstream infection 
as per ICU attending OR culture-positive recovery of the same organism from the dialysis 
catheter upon removal. 
 
3 - Ultrasonographically-confirmed thrombus attributed to CVC 
Defined as: Any confirmed occlusive or non-occlusive thrombus in the vein in which a CVC 
for RRT was placed (or remains in place) or in the venous system drained by the vein in 

 
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which the CVC was placed; further qualified by pulmonary embolism as a result of 
thrombus. 
 
4 - Pneumothorax (for catheters placed in the internal jugular or subclavian positions)  
Defined as: Air in the pleural space on routine chest x-ray that is performed following CVC 
insertion; further qualified by requirement for chest tube placement. 
 
5 - Hemothorax (for catheters placed in the internal jugular or subclavian positions)  
Defined as: Blood in the pleural space following CVC insertion; further qualified by 
requirement for chest tube placement. 
 
6 - Air embolism 
 
7 - Inadvertent arterial puncture at time of CVC insertion 
 
8 - Other CVC-related safety events 
 
2.6 Safety outcomes  
All deaths that occur during the 14-day follow-up period will be reviewed by the local 
investigators in coordination with attending clinicians in order to determine whether these may 
be linked to participation in the trial. We will also collect data on safety events with a focus on 
those related to the administration of RRT and the associated need for vascular access as 
described above. The local research team will determine whether these events qualify as 
serious adverse events (see definition below). 
 
2.6.1 Definition of a serious adverse event 
The standard definition of a serious adverse event (SAE) includes any adverse event that 
meets at least one of the following conditions:  
- is fatal (results in death) 
- is felt to be life-threatening 
- requires in-patient hospitalization or prolongation of an existing hospitalization 
- results in significant disability or incapacity 
 
For this study, a reportable SAE must meet the definition noted above and also be 
considered45: 
i. 
an atypical event, defined as clinically significant and unexpected in the context of 
critical illness secondary to AKI, AND;  
ii. 
an event that is at least possibly related to study procedures. 
 
For reportable SAEs that occur from the time of patient consent/enrollment until Day 14, the 
following reporting procedure applies: 
- 
Report using the Adverse Event Form of the eCRF within 1 business day of 
becoming aware of the event.  
- 
Document in source records. 
- 
Follow-up of any SAE that is fatal or life threatening should be provided within 7 
calendar days. 

 
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- 
Follow-up the outcome of SAEs until clinical recovery is complete and laboratory 
results have returned to baseline, or until progression has been stabilized. Follow-up 
will continue for the duration of the patient’s study participation. 
 
Local reporting requirements may differ from those of the trial. The local investigator will be 
responsible for reporting SAEs to their Ethics Board as per institutional requirements. 
 
 
2.7 Measurement of outcomes 
2.7.1 Primary outcome 
We will access hospital records (both study hospital and facilities to which patients may be 
transferred), consult primary care physicians, contact participants/SDMs, and if needed, 
access death registries to ascertain vital status at 90 days. 
 
2.7.2 Secondary outcomes 
1 - RRT dependence will be defined by the receipt of any form of RRT within +/- 14 days of the 
90-day time point following randomization. 
2 - The composite outcome of death by Day 90 (primary outcome) or RRT dependence at Day 
90 (principal secondary outcome). 
3 - We will evaluate kidney function 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 value from Day 90 minus 14 days or 
Day 90 plus 42 days). eGFR will be derived from the CKD-EPI equation and expressed in 
mL/min/1.73 m2.42  
4 - A urine sample will be obtained at Day 90 (or as close as possible to Day 90) and not 
beyond 132 days after randomization (i.e., Day 90 minus 14 days or Day 90 plus 42 days) 
for assessment of spot albumin and creatinine concentrations. 
5 - Major adverse kidney event (MAKE) by Day 90 (defined as the composite of death, RRT 
dependence or sustained reduction in kidney function [defined as Day 90 eGFR < 75% 
baseline eGFR]). 
6 - A ventilator-free day will be defined as the receipt of < 2 hours of either invasive or non-
invasive ventilation within a 24-hour period. 
7 - A vasoactive-free day will be defined as < 2 hours of receipt of any vasoactive therapy 
provided by continuous infusion within a 24 hour period. 
8 - An ICU-free day will be defined as admission to an ICU for < 2 hours within a 24 hours 
period. 
9 - Hospital-free days will be defined as a 24-hour period completely free of an inpatient 
hospitalization. 
10 - Death in ICU, at 28-days and in-hospital will be compared between the groups. 
11 - The EuroQol EQ-5D-5L questionnaire will be used to measure health-related quality of 
life. As a widely accepted measure of patient utility, the EQ-5D-5L can be converted to 
quality-adjusted life years (QALYs) for use in the economic evaluation. 
12 - The economic evaluation will include the cost of the strategy itself (which will be assessed 
using a micro-costing approach46), plus any implications on length of stay, safety events 
associated with an accelerated or standard initiation strategy, and the costs associated 
with RRT use after ICU discharge up to 365 days from randomization. To measure these 

 
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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 
multicentre clinical trial, valuation of costs will be done for the subset of all patients 
enrolled within the province of Alberta, Canada (extrapolated based on resource use for all 
patients in the trial) using administrative costing data available from Alberta Health 
Services, and from the Alberta Physicians’ fee schedule, using methods familiar to study 
investigators46. 
13 - In jurisdictions where this is feasible, we will access administrative data to ascertain vital 
status and the need for RRT at Day 365 from randomization. RRT dependence will be 
defined by the patient having a kidney transplant or the receipt of any form of RRT within 
+/- 14 days of the 365-day time point following randomization.  
 
2.8 Health resource utilization analysis  
Given that a strategy of accelerated RRT initiation is likely to increase short-term resource use, 
assessing the implications on long-term health outcomes and costs is important. Since we will 
be assessing survival, RRT dependence, patient utility, and costs, we will be able to conduct a 
full economic evaluation of accelerated RRT initiation in patients who have AKI.  
 
Consistent with current guidelines, we will use the perspective of the publicly funded health 
care system. As noted above, we will carefully measure the cost of the intervention, as well as 
any associated and downstream costs. We will also estimate “time and travel” costs for 
patients in the trial, based on the subsequent need for RRT therapy.48 
 
If RRT dependence at 90 days differs between the two treatment arms, then extrapolation of 
the benefits and costs beyond the timeframe of the clinical trial will be required to assess the 
complete economic implications of this strategy. This will be critical to justifying (or not) the use 
of this strategy to health care payers. To enable this, a decision analytical framework will be 
developed alongside the data from the clinical trial to model the potential impact of accelerated 
RRT initiation on long-term outcomes and costs, using a lifetime perspective. Sensitivity 
analysis will be undertaken to account for uncertainty regarding the long-term estimated costs 
and effects.  
 
 
2.9 Sample size justification 
We expect a 90-day mortality of 40% in the standard arm. This mortality rate is compatible with 
90-day mortality reported in contemporary cohorts of patients with RRT-requiring AKI in 
Finland and Australia/New Zealand.4,21 There is no clear guidance on the estimated risk 
reduction afforded by accelerated RRT so we have selected a relative risk reduction of 15% 
(absolute risk reduction 6%) as recommended by experts to be an effect magnitude that is 
minimally important and conceivable with this intervention.49 With Type I error of 0.05 and 
power of 0.90, a sample size of 1,359 patients/arm would be required (total 2,718). In order to 
account for the interim analyses, the required sample size increases to 2,780. After accounting 
for a combined rate of crossover and dropouts of 3% (as derived from the pilot phase), we will 
target a total sample size of 2,866. 
 

 
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2.10 Analysis plan 
Baseline data will be summarized descriptively. The primary outcome of 90-day mortality will 
be evaluated using an intent-to-treat approach. A simple comparison of proportions will be 
performed using a chi-squared test. The risk ratio and relative risk reduction will be estimated 
with 95% confidence intervals. An adjusted analysis will also be completed using logistic 
regression and will include the following baseline variables: age, sex, sepsis, receipt of 
cardiopulmonary bypass and SOFA score. 
The principal secondary outcome, the proportion of survivors who are RRT dependent at 90 
days, presents challenges as the non-inclusion of participants who died might obviate the inter-
group balance afforded by randomization. We will consider two complementary approaches to 
examine this question. First, we will use the adjusted model for the primary outcome to 
estimate the probabilities of 90-day survival. We will then use the reciprocals of these as 
weights in a logistic regression for RRT, resulting in an inverse probability weighted analysis. 
This is typically called a marginal structural model. The second approach will employ a 
multinomial regression model to jointly consider the states: dead at 90 days, alive at 90 days 
receiving RRT and alive at 90 days RRT-free. A similar approach will be used to estimate the 
probabilities of 365-day survival and to consider the states: dead at 365 days, alive at 365 
days receiving RRT and alive at 365 days RRT-free. 
 
Duration of ventilation, vasoactive therapy, ICU stay and hospitalization and albuminuria at 90 
days (expressed as the urinary albumin to creatinine ratio in mg/mmol) will be compared by 
means of a t-test. Finally, eGFR decline of 25%, death in ICU, by 28 days and in-hospital, and 
ICU readmission and rehospitalization within 90 days will be compared by chi-squared tests. 
 
Interim analyses for efficacy based on the primary outcome will be done when 25, 50 and 75% 
of planned enrollees have completed 90-day follow-up. Given the risks of false positive results 
with early stopping for benefit, statistical significance will be declared using small p-values 
established by O’Brien-Fleming boundaries on the primary outcome (90-day mortality). A 
detailed monitoring plan will be developed in consultation with the DSMB prior to 
commencement of recruitment.  
 
We will evaluate the effect of accelerated vs. standard RRT in the following a priori defined 
subgroups: i) patients with sepsis (based on the possibility that earlier RRT, due to more 
aggressive removal of inflammatory mediators, might have a more prominent effect among 
patients with sepsis-associated AKI);  ii) patients whose baseline eGFR is < 45 mL/min/1.73 
m2 (based on the possible modifying effect of pre-existing chronic kidney disease on mortality 
and progression to chronic RRT dependence) and iii) region of the world- Canada/US vs 
Australia/NZ vs Europe (based on possibility that regional RRT and/or critical care practices 
have a modifying effect on the impact of the intervention on outcomes). 
 
 
2.11 Planned recruitment rate and methods to ensure enrollment 
We anticipate a recruitment rate of 1-2 participants/site/month. Based on a conservative 
estimate, we should be able to recruit the target population within 3 years. Site coordinators 
will screen patients in the critical care unit every weekday morning and afternoon and identify 
eligible patients. An attempt will then be made to obtain consent.  

 
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The participating centers have large critical care programs with extensive experience in the 
administration of RRT to patients with AKI. Each site also has a team of skilled ICU research 
coordinators who have successfully enrolled patients into numerous multicentre trials, 
including some in the area of AKI.  
 
We are also proposing several steps to ensure this trial’s success including: 1) Site Education: 
Prior to the trial start up at each centre, the principal investigators will visit each site and 
present rounds to clinicians and nurses on the rationale, design, and logistics of the STARRT-
AKI trial. 2) Monitoring of Recruitment: The central trial coordinating centre will conduct regular 
surveillance, monitoring and reporting of recruitment activity at each participating site, and 
distribute regular newsletters and progress reports. We also propose to hold regularly 
scheduled investigator and research staff meetings. 3) Novel consent models: The need to 
assure the rapid enrollment of eligible patients is of particular importance in a trial that is 
testing the value of early/accelerated RRT initiation. The burden of illness in our eligible 
population is such that in most cases, the substitute decision maker (SDM) will need to be 
approached for consent. This SDM may often be unavailable at the time the potential 
participant is found to meet eligibility criteria. In these situations, and where permitted by the 
Ethics Board, we will try to obtain consent by phone to enable recruitment of patients whose 
SDMs cannot attend the hospital in-person. At centres where this has been approved by the 
Ethics Board, if SDMs are not available or readily contactable, eligible patients may be 
recruited through a process of deferred/delayed consent.  
 
 
2.12 Co-Enrollment 
Patients recruited to STARRT-AKI may also be enrolled in other studies or clinical trials as 
long as those studies/trials do not interfere with the timing of RRT initiation mandated by the 
STARRT-AKI protocol. Furthermore, the therapy tested in the other trial must not have a 
plausible interaction with the timing of RRT initiation. Investigators and coordinators will 
routinely review trials that are operating in parallel in the study ICUs. The trial Steering 
Committee will review and approve co-enrollment in other studies on a case-by-case basis.50 
 
 
2.13 Study centres 
This will be an international initiative comprising up to 100 centres and in up to 15 countries. 
 
 
2.14 Mitigation of bias 
Institution of a sham/placebo RRT would be ethically and logistically difficult and hence 
blinding is impractical. However, we will take several steps to mitigate bias. Central computer-
based randomization will be concealed. The use of random treatment blocks will prevent 
investigators and site coordinators from predicting the treatment assignment for the 
subsequent eligible patient.  
 
To minimize the impact of co-interventions, a major concern when investigators and clinicians 
are unblinded to the trial-mandated intervention, the protocol calls for all delivered RRT to 

 
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follow guidelines that are consistent with contemporary evidence-based practice. As done in a 
recent RCT, the protocol calls for RRT modality to be modified with the evolving hemodynamic 
state of the participant,20 although the balance of evidence at the current time does not 
suggest the superiority of any RRT modality even in hemodynamically unstable patients.23,24  
Two recently published landmark trials have not demonstrated any benefit of “intensive” or 
“high dose” RRT in the setting of AKI.20,21 Our RRT prescription guidelines reflect the range of 
doses that were administered in these trials but also specify minimum doses for each modality. 
For patients receiving IHD and SLED, session duration needs to be a minimum of 3 and 8 
hours, respectively with a session frequency of at least 3 times/week. The minimum prescribed 
effluent dose in CRRT is 20 mL/kg/hr (averaged over a 24 hr period). We have also been 
deliberately liberal with respect to the choice of clearance mode (hemodialysis vs 
hemofiltration vs hemodiafiltration) given the fact that local practices may vary based on the 
availability of technology and the opinion of local clinicians. A recent meta-analysis did not 
demonstrate the superiority of any clearance mode in the setting of AKI.26 Strict criteria for 
RRT cessation have been established. Together, these measures will ensure that once RRT is 
started, patients in both treatment arms receive RRT according to identical principles. 
Since the study arm will be apparent to investigators from the outset, the risk of clinician-
directed crossover is a concern, with participants being switched to the treatment arm that is 
perceived to be more “beneficial” or “appropriate”. The patient’s changing clinical needs must 
always supersede adherence to the study protocol and some crossovers are thus unavoidable. 
However, concerns about crossovers are mitigated from our experience in the pilot phase of 
the trial. Only 3/48 patients assigned to accelerated RRT commenced RRT > 12 hours from 
eligibility. Importantly, no patients assigned to standard RRT initiated RRT within 12 hours of 
eligibility and among those patients who did commence RRT, the median time from eligibility to 
RRT initiation was 31 hours. In this trial, crossovers will be documented and reasons for 
crossover will be elicited from treating clinicians and reported and reviewed by both the trial 
Steering Committee and the DSMB. 
Most importantly, outcome assessment will not be significantly affected by the lack of blinding, 
especially the primary outcome of all-cause mortality. 
 
SECTION  3. TRIAL MANAGEMENT 
 
3.1 The Coordinating Centre 
The Coordinating and Data Management Centre is the Applied Health Research Centre of the 
Li Ka Shing Knowledge Institute (www.ahrconline.com) of St. Michael’s Hospital in Toronto, 
Canada. This comprehensive trials unit employs expert project management staff. The 
Coordinating Centre will be responsible for developing and programming the electronic case 
report forms, trial procedure manual, data monitoring, regulatory documents, data 
management and analysis, and providing progress and data reports to the Steering 
Committee, Data Safety and Monitoring Board, and participating sites. The Applied Health 
Research Centre staff is highly familiar with the STARRT-AKI protocol as they managed the 
pilot phase of the trial. 
 

 
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3.2 Role of the site investigators  
The site investigators will be responsible for: a) obtaining local institutional review board / 
research ethics board approval and ensuring the ethical conduct of the trial, b) publicizing the 
study to all intensivists, nephrologists, trainees, and ICU nurses c) ensuring that eligible 
patients consenting to the trial are randomized, d) ensuring that all randomized patients are 
followed according to protocol, and e) ensuring that serious adverse events are promptly 
transmitted to the Methods Centre and Ethics Board, with follow-up enquiries addressed in a 
timely manner. 
 
3.3 Role of the local study coordinators 
The site study coordinators will be responsible for: a) identification of eligible patients, 
recruitment and consent; b) providing day-to-day guidance to the ICU team (physicians and 
nurses) regarding adherence to study protocols, c) providing appropriate follow-up for all study 
patients, completing the fields in the data forms and ensuring the meticulous and secure 
storage of information and d) maintaining a screening log of all eligible patients. 
 
3.4 Steering Committee 
As co-principal investigators, Ron Wald and Sean Bagshaw will assume overall responsibility 
for all operational aspects of the trial, including acquisition and administration of funds, training 
of research staff, supervision of trial implementation, data interpretation and completion of the 
final manuscript. Senior investigators with an extensive background in Critical Care 
Nephrology and clinical trials will oversee the trial in Canada (Neill Adhikari22,25,51 , Matthew 
Weir52 and Francois Lamontagne53-57), the United States (Kathleen Liu28,62 and Paul 
Palevsky20,58-60), Europe (Michael Joannidis61-63, Marlies Ostermann64-67 Ville Pettila4,68-70, 
and Alistair Nichol71-74) and Australia/New Zealand (Rinaldo Bellomo21,75-77, Martin 
Gallagher78-81 and Shay McGuiness82,83). Braden Manns is a nephrologist at the University 
of Calgary and a health economist who has published extensively on the costs of novel 
therapies in Nephrology, including the application of RRT in the setting of AKI.16,46,48,84 He will 
supervise an evaluation of the implications of the treatment strategies on health resource 
utilization. Orla Smith, Research Manager for Critical Care at St. Michael’s Hospital, 
operationalized the screening process and developed data collection tools for this research 
program.40,85,86 She will oversee the practical training of research staff. Kevin Thorpe is the 
head of biostatistics at the AHRC and an assistant professor at the Dalla Lana School of 
Public Health, University of Toronto, with expertise in kidney disease-oriented studies, 
including prior trials conducted by our group, and an internationally recognized expert in the 
design and execution of pragmatic trials.25,87-89 He will generate the randomization protocol, 
and conduct or oversee all the interim and final analyses as well as any additional analyses 
requested by the DSMB. 
 
3.5 Data safety and monitoring board 
A DSMB will be established, consisting of 5 members with expertise in Nephrology, Critical 
Care and trial methodology. Members will meet at least every 6 months while the trial is 
recruiting patients to review all serious adverse events separately and in aggregate. The 
DSMB Chair will communicate with the principal investigators after each meeting. The DSMB 
will also review results of the interim analyses described above and make recommendations to 
the Steering Committee, based on the a priori stopping rules. A DSMB charter will be drafted. 

 
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3.6 Sub-studies 
The Steering Committee will establish a sub-committee to consider potential sub-studies, 
some of which will require additional funding beyond the core trial funding to accomplish the 
stated objectives of the trial. Proposed sub-studies may include but are not limited to the 
following: 
 
1. Long-term survival/renal function (1-5 years) 
2. Long-term costs/resource use (1-5 years) 
3. Mechanistic/pharmacological substudies 
4. Fluid balance substudy 
5. Novel kidney damage biomarker substudy 
6. Weaning from mechanical ventilation support substudy 
 
3.7 Ethics and consent issues 
Ethics Board approval will be secured prior to the commencement of screening activities at 
each centre. Study coordinators will be responsible for obtaining informed consent from the 
eligible patient or the substitute decision maker (SDM) if the patient is incapable. If the SDM 
provides consent but the patient becomes capable prior to the end of the follow-up period, the 
study coordinator will seek consent directly from the patient, who will have the option of 
withdrawing from the study. If a SDM is contactable by phone but is not able to come in person 
to sign the consent form, steps will be taken to obtain phone consent for the study.  
 
At sites where this has been approved by the local Ethics Board, patients who are eligible but 
incapable of providing consent and for whom an SDM is not available may be enrolled and 
randomized through a process of deferred/delayed consent. In this circumstance, a dedicated 
effort will be made to locate a SDM even after recruitment has taken place and the SDM -once 
found- will be given the option of affirming or withdrawing the patient’s participation. In 
addition, once the participant regains capacity, he/she will be asked to affirm or withdraw 
consent for the trial. 
 
The time of eligibility will be documented on the study screening log. Consent (or 
documentation of enrollment in the case of deferred/delayed consent) must be obtained within 
12 hours of this time, otherwise the patient’s eligibility will have elapsed and the patient will not 
be included in the trial. 
 
To ensure confidentiality, patients will be identified to the Methods Centre only by their study 
identification number. The site study coordinator will keep a master list of patient names and 
identification numbers in a password-protected computer file. At the end of the study, master 
lists will be destroyed. In accordance with current requirements, we will store data for a 
minimum of 10 years. 
 
3.8 Publication and authorship policy 
Members of the Steering Committee will participate in drafting the manuscript that describes 
the main findings of the STARRT-AKI trial (i.e., the “principal paper”). All investigators will be 
asked to review and provide input on the final manuscript and will be invited to serve as co-

 
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authors. It is anticipated that the principal paper’s authorship will be attributed collectively to 
“The STARRT-AKI Investigators”. 
 
Authorship on STARRT-AKI publications (principal paper and papers emanating from sub-
studies) will adhere to the Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals of the International Committee of Medical Journal Editors.90 These Requirements 
state “Authorship credit should be based on 1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; 2) drafting the article or 
revising it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors should meet conditions 1, 2, and 3.”  
 
 

 
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