A randomized, placebo-controlled, double-blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design

Boyer, Thomas D.; Medicis, Joseph J.; Pappas, S. Chris; Potenziano, Jim; Jamil, Khuramm

doi:10.2147/oajct.s31844

Cited by 3 publications

(3 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In REVERSE, study discontinuation was required for patients experiencing any ischemic event. 13,16 In CONFIRM, patients who experience cardiac or mesenteric ischemia will be discontinued from the study, but those experiencing a reversible peripheral or skin ischemic adverse event will be allowed to continue. Also, because new diagnostic criteria for HRS eliminate the strict 221 μmol/L (2.5 mg/dL) SCr threshold in lieu of changes over time, 17 the inclusion criteria for participation in CONFIRM were modified such that the threshold for the second SCr value is 199 μmol/L (2.25 mg/dL), rather than 221 μmol/L (2.5 mg/dL) as in previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…The parallel-group study design of CONFIRM is substantially similar to that of REVERSE (Figure 1). 16 CONFIRM patients are required to be at least 18 years of age, have a diagnosis of cirrhosis and ascites, and demonstrate rapidly progressive worsening of renal function to a serum creatinine (SCr) level of ≥199 μmol/L (≥2.25 mg/dL), with a trajectory for SCr to double over 2 weeks, as determined using the same nomogram as REVERSE. 16 Exclusion criteria for CONFIRM are consistent with the previously reported studies, 12,16 with a few exceptions.…”

Section: Overview Of Study Methodology and Primary End Pointmentioning

confidence: 99%

“…16 CONFIRM patients are required to be at least 18 years of age, have a diagnosis of cirrhosis and ascites, and demonstrate rapidly progressive worsening of renal function to a serum creatinine (SCr) level of ≥199 μmol/L (≥2.25 mg/dL), with a trajectory for SCr to double over 2 weeks, as determined using the same nomogram as REVERSE. 16 Exclusion criteria for CONFIRM are consistent with the previously reported studies, 12,16 with a few exceptions. Importantly, unlike in the previous studies, patients with one or more events of large-volume paracentesis of ≥4 L within 2 days of randomization, and those with transjugular intrahepatic portosystemic shunt within 30 days of randomization are excluded from CONFIRM; patients with microhematuria in the setting of urinary catheterization and those receiving octreotide and midodrine up to the time of enrollment are eligible for CONFIRM.…”

Section: Overview Of Study Methodology and Primary End Pointmentioning

confidence: 99%

See 2 more Smart Citations

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

Jamil¹,

Pappas²,

Sanyal³

2019

OAJCT

View full text Add to dashboard Cite

Background: Hepatorenal syndrome type 1 (HRS-1) is an uncommon, rapidly progressing, potentially fatal renal failure if left untreated. Terlipressin is a vasopressin analog that is first-line therapy in combination with albumin for treatment of HRS-1 in countries outside of North America. In two previous Phase III clinical trials, terlipressin showed favorable effects on improvement in renal function compared with placebo; however, neither study showed a significant between-group difference in the primary end point. CONFIRM (NCT02770716) is an ongoing clinical trial designed to address operational challenges observed in the previous studies by using a novel, more clinically relevant primary end point than the previous studies. Methods: This Phase III, randomized, double-blind, multicenter study is expected to enroll about 300 patients at approximately 70 sites in the US and Canada. Patients with cirrhosis and ascites demonstrating renal impairment via rapidly progressive worsening of serum creatinine (SCr) level (≥199 μmol/L [≥2.25 mg/dL] with a trajectory of SCr doubling over 2 weeks) are randomized 2:1 to receive either terlipressin 1 mg every 6 hrs as an IV bolus injection or placebo. The design of the study is generally similar to previous terlipressin prospective studies in the setting of HRS-1. A key feature differentiating this study from the previous ones centers around a novel, multi-component efficacy variable that extends beyond the traditional outcome of improvement in renal function to include durability of treatmentrelated effects on renal replacement therapy (RRT) requirements and survival. To meet criteria for the primary efficacy end point in CONFIRM, patients must show not only HRS reversal confirmed by two SCr values ≤1.5 mg/dL, but also survive, without RRT, for at least 10 days after achieving it. Conclusion: Data from this pivotal study will demonstrate whether terlipressin treatment is effective as measured by a new, clinically meaningful, multi-component primary efficacy end point.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Overview Of Study Methodology and Primary End Pointmentioning

confidence: 99%

Section: Overview Of Study Methodology and Primary End Pointmentioning

confidence: 99%

See 1 more Smart Citation

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

Jamil¹,

Pappas²,

Sanyal³

2019

OAJCT

View full text Add to dashboard Cite

show abstract

Hepatorenal syndrome: pathophysiology and evidence-based management update

Hasan

Rashid

Chirilă

et al. 2021

Romanian Journal of Internal Medicine

View full text Add to dashboard Cite

Hepatorenal syndrome (HRS) is a functional renal failure that develops in patients with advanced hepatic cirrhosis with ascites and in those with fulminant hepatic failure. The prevalence of HRS varies among studies but in general it is the third most common cause of acute kidney injury (AKI) in cirrhotic patients after pre-renal azotemia and acute tubular necrosis. HRS carries a grim prognosis with a mortality rate approaching 90% 3 month after disease diagnosis. Fortunately, different strategies have been proven to be successful in preventing HRS. Although treatment options are available, they are not universally effective in restoring renal function but they might prolong survival long enough for liver transplantation, which is the ultimate treatment. Much has been learned in the last 2 decades regarding the pathophysiology and management of this disease which lead to notable evolution in the HRS definition and better understanding on how best to manage HRS patients. In the current review, we will summarize the recent advancement in epidemiology, pathophysiology and management of HRS.

show abstract

Norepinephrine is More Effective Than Midodrine/Octreotide in Patients With Hepatorenal Syndrome-Acute Kidney Injury: A Randomized Controlled Trial

2021

View full text Add to dashboard Cite

Background: Terlipressin is the first-line pharmacological treatment for hepatorenal syndrome. When terlipressin is unavailable, midodrine/octreotide or norepinephrine, with albumin, represent the alternative treatments. The comparative efficacy of these alternative regimens remains unclear.Objective: To compare the efficacy of midodrine/octreotide to that of norepinephrine for the treatment of patients with hepatorenal syndrome.Methods: In the intensive care setting, sixty patients with hepatorenal syndrome were randomized to initially receive either 0.5 mg/h of norepinephrine (maximum 3 mg/h) or 5 mg of oral midodrine three times/day (maximum 12.5 mg three times/day) plus octreotide (100 μg/6 h) as subcutaneous injection (maximum 200 μg/6 h), together with albumin (20–40 g/day). Treatment was allowed for a maximum of 10 days. Survival was analyzed for up to 30 days. The primary efficacy outcome was the proportion of patients who achieved full response, defined as the return of serum creatinine to a value within 0.3 mg/dl of the baseline at the end of treatment.Results: There was a significantly higher rate of full response in the norepinephrine group (15/26, 57.60%) than the midodrine/octreotide group (5/25, 20%) (p = 0.006). Eleven (42.30%) patients in the norepinephrine group and 6 (24%) in the midodrine/octreotide group survived (p = 0.166).Conclusion: Norepinephrine plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with hepatorenal syndrome.(ClinicalTrials.gov, identifier: NCT03455322).https://clinicaltrials.gov/ct2/show/NCT03455322?cond = Hepatorenal+Syndrome&cntry = EG&draw = 2&rank = 1.

show abstract

A randomized, placebo-controlled, double-blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design

Cited by 3 publications

References 40 publications

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

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

Hepatorenal syndrome: pathophysiology and evidence-based management update

Norepinephrine is More Effective Than Midodrine/Octreotide in Patients With Hepatorenal Syndrome-Acute Kidney Injury: A Randomized Controlled Trial

Contact Info

Product

Resources

About