Verified Hepatorenal Syndrome Reversal As A Robust Multi-Component Primary End Point: The CONFIRM Study Trial Design

Figures & data

Table 1 Overview Of Key Differences Between The Study Designs Of OT-0401, REVERSE, And CONFIRM

Study Design	OT-0401^Citation12	REVERSE^Citation13,^Citation16	CONFIRM
Primary end point	Resolution of HRS (SCr ≤133 μmol/L^a on two occasions ≥48 hrs apart) without RRT, death, or recurrence of HRS-1 on or prior to Day 14	Confirmed HRS reversal (2 SCr ≤133 μmol/L^a ≥40 hrs apart [48 hrs minus an 8 hr window]) while on study treatment + without RRT or liver transplant	Verified HRS reversal (2 consecutive SCr ≤133 μmol/L^a ≥2 hrs apart) while on study treatment + alive without RRT for ≥ 10 days
Statistical methods	1:1 randomization	1:1 randomization	2:1 randomization
Sample size	n=112	n= 196	n=300
Threshold for second SCr	≥221 μmol/L^b	≥221 μmol/L^b	≥199 μmol/L^c
Prior vasopressor use	No exclusion for prior vasopressor exposure	Patients with exposure within 48 hrs prior were excluded	No exclusion for midodrine/octreotide exposure
History of TIPS	Not specified	Not specified	Patients with TIPS within 1 month prior were excluded
LVP status at study entry	Not specified	Not specified	Patients with prior LVP of ≥4 L within 48 hrs prior were excluded
Rule out intrinsic kidney disease	Not specified	Any microhematuria was excluded	Microhematuria in setting of urinary catheterization was allowed
Dose administration for reversible adverse events	Not specified	Study drug permanently discontinued for any ischemic event	Study drug could be resumed at lower dose (0.5 mg) in patients with reversible peripheral ischemic adverse events
Specific instructions for fluid overload	Not specified	Not specified	Study investigators were instructed on judicious use of diuretics prior to opting for RRT
Randomization stratification	Baseline alcoholic hepatitis	Baseline SCr and alcoholic hepatitis	Baseline SCr and prior LVP of ≤4 L
Biomarkers for AKI	Not performed	Not performed	Urine and plasma sample for AKI (optional substudy)

Notes:

a 1.50 mg/dL;

b 2.50 mg/dL:

c 2.25 mg/dL.

Abbreviations: AKI, acute kidney injury; HRS, hepatorenal syndrome; LVP, large-volume paracentesis; RRT, renal replacement therapy; SCr, serum creatinine; TIPS, transjugular intrahepatic portosystemic shunt.

Figure 1 CONFIRM study design. Copyright © 2012. Dove Medical Press. Adapted from Boyer TD, Medicis JJ, Pappas SC, Potenziano J, Jamil K. A randomized, placebo-controlled, double-blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design. Open Access J Clin Trials. 2012;4:39–49.¹⁶

Abbreviation: R, randomization.

Figure 2 Overview of the multi-component primary end point in CONFIRM. ^aVerified reversal is assessed as percentage of patients achieving this end point on terlipressin vs placebo; open-label albumin is administered in both treatment groups. ^bTreatment period is up to Day 14 or discharge, whichever comes first.

Abbreviations: HRS, hepatorenal syndrome; RRT, renal replacement therapy; SCr, serum creatinine.

Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology. 2008;134(5):1360–1368. doi:10.1053/j.gastro.2008.02.014

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Boyer TD, Sanyal AJ, Wong F, et al. Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1. Gastroenterology. 2016;150(7):1579–1589. doi:10.1053/j.gastro.2016.02.026

 PubMed Web of Science ®Google Scholar

Boyer TD, Medicis JJ, Pappas SC, Potenziano J, Jamil K. A randomized, placebo-controlled, double-blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design. Open Access J Clin Trials. 2012;4:39–49. doi:10.2147/OAJCT.S31844

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