Multicenter, Randomized Phase 2B Study to Evaluate the Efficacy,Safety and Tolerability of OCR-002 (ornithine phenylacetate) inHospitalized Patients with Cirrhosis and AssociatedHyperammonemia with an Episode of Hepatic Encephalopathy - STOP-HE study
- Conditions
- Hepatic encephalopathyMedDRA version: 17.0Level: PTClassification code 10019660Term: Hepatic encephalopathySystem Organ Class: 10029205 - Nervous system disordersTherapeutic area: Diseases [C] - Nervous System Diseases [C10]
- Registration Number
- EUCTR2013-005412-10-IT
- Lead Sponsor
- Ocera Therapeutics Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 231
Overall hospitalized patients with cirrhosis and overt Stage 2, 3, or 4 hepatic encephalopathy resulting from any precipitating factor are allowed to enroll within the confines of eligibility caveats detailed below (e.g., patients with gastrointestinal bleeding, infection, transjugular intrahepatic portosystemic shunt etc may all enroll if stipulations of inclusion/exclusion criteria are met). Patients intubated only for airway protection are allowed to enroll provided requirements (below) are met.
Note that the target time window for randomization is within 24 hours of hospital diagnosis of HE (10% variance allowed). There is a special allowance case-by-case with medical monitor review for an extension in this time interval for Stage 3 or Stage 4 HE (please see Section 6.1 and 6.2 for details).
• 18–75 years with HE admitted to hospital (eg, via emergency department or direct admission, etc)
• Evidence of/known cirrhosis – The diagnosis of liver cirrhosis will be based on clinical, radiological, or histological criteria
• Hospitalized with an acute episode of hepatic encephalopathy as complication of cirrhosis
• Venous ammonia = 1.3 times the upper limit of normal at Screening
• Acute HE episode defined by Stage = 2 (Hepatic Encephalopathy Staging Tool, Appendix A) at both Screening and baseline (pre-randomization). At the end of a prerequisite minimum 12-hour interval from hospital HE diagnosis to start of Screening patients must still be clearly overtly encephalopathic and during the Screening/Baseline Period have no improvement (decrease in Hepatic Encephalopathy Stage). During the 12-hour pre-Screening period in order to qualify the patient must consistently manifest hepatic encephalopathy that is clearly overt and equivalent to at least Stage 2 using the Hepatic Encephalopathy Staging Tool (Appendix A). – Breakthrough HE occurring during prophylaxis with rifaximin of at least 1 week duration is allowed and in this case dosing with rifaximin may be continued on study (de novo treatment of HE episode with rifaximin is not allowed). If only one dose of rifaximin has been administered prior to Screening to a patient with an acute HE episode naïve to rifaximin (ie, who was not previously receiving rifaximin for HE prophylaxis for at least 1 week) that patient may still randomize (if eligible) if no more rifaximin is given. See Section 5.4 for further details.
• Patients with transjugular intrahepatic portosystemic shunt (TIPS) are allowed
• Women of child-bearing potential must have negative serum pregnancy test
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 110
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 30
• Not expected to survive 2 weeks (note patients with malignancy, e.g. hepatocellular carcinoma, exceeding this life expectancy may enroll)
• Type 1 hepatorenal syndrome characterized by rapidly progressive reduction in renal function as defined by a doubling of the initial serum creatinine to a level > 3 mg/dL or a 50% reduction of the initial 24-hour creatinine clearance to a level <20 mL/min in less than 2 weeks.
• Hyponatremia (sodium < 125 mmol/L)
• Renal failure with serum creatinine > 3 mg/dL (265.2 µmol/L) or need for hemodialysis, peritoneal dialysis, or continuous venovenous hemofiltration at Screening
• New York Heart Association (NYHA) Class 3 or 4 congestive heart failure or overt clinical signs of congestive heart failure
• Patients requiring mechanical ventilation may enroll if they are electively intubated only for airway protection (to prevent aspiration) due to severe HE and do not require ongoing sedation. Transitory intubation with sedation for specific procedure/intervention anticipated to be < 24 hours is allowed. The following ventilator settings would exclude a patient: (a) fraction of inspired oxygen (FiO2) > 0.5 (> 50% oxygen); (b) positive end-expiratory pressure (PEEP) > 10 cm H2O (water). The intent is to exclude patients requiring intubation for respiratory failure or severe pneumonia. Note continuous positive airway pressure (CPAP) is allowed.
• Any prior stroke with cognitive sequelae
• Acute alcoholic hepatitis (current hospital admission)
• Schizophrenia, dementia, or other severe psychiatric disorders that would interfere with evaluation of hepatic encephalopathy
• Presentation to hospital with acute alcohol or drug intoxication (patients with alcoholic liver disease/cirrhosis due to alcohol are allowed). Inebriated patients and those with acute effects of alcohol at presentation, by immediate prior history, overall clinical evaluation, or blood alcohol level = 1.6 g/L (0.16% w/v, 160 mg/dL, 34.74 mmol/L) are excluded. Patients with symptoms of serious alcohol withdrawal at either Screening or Baseline are excluded.
• Patients with gastrointestinal bleeding may enroll. However, active upper gastrointestinal bleeding at the time of enrollment that has not been addressed by definitive endoscopic treatment or appropriate medical therapy and remains uncontrolled (requiring > 2 units packed red blood cells per day on a continuing ongoing basis) will exclude a patient; patients whom the physician considers likely to die of gastrointestinal bleeding should be excluded. Those with bleeding from portal hypertensive gastropathy may enroll provided they are within above confines.
• Hemodynamic instability, defined as a mean arterial pressure of <60 mm Hg and/or evidence of poor organ perfusion or the use of more than one (1) vasopressor to support blood pressure. Terlipressin, vasopressin (and analogs), and octreotide (and somatostatin analogs) are allowed to address complex vascular dynamic issues specific to this population (eg, variceal bleeding, renal perfusion). However, if more than one (1) vasopressor is being given for hemodynamic support of unstable mean arterial pressure (ie, implying shock and sequelae) this makes the patient ineligible.
• Corrected QT interval calculated using Fridericia’s formula (QTcF) > 500 msec at screening
• Concomitant administration of drugs known to interfere with renal excretion of phenylacetylglutamine (PAGN), such as probenecid. Use of L-ornithine L-aspartat
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method