A multicenter, randomized clinical study to see how efficient, safe and well tolerated OCR-002 new drug candidate is in patients who suffer from cirrhosis and high ammonia level in blood with an onset of encephalopathy caused by abnormal liver activity

• Register: EUCTR
• Last refreshed on: 13 February 2017
• Main ID: EUCTR2013-005412-10-AT
• Date of registration: 07/07/2014
• Prospective Registration: Yes
• Primary sponsor: Ocera Therapeutics Inc
• Public title: A multicenter, randomized clinical study to see how efficient, safe and well tolerated OCR-002 new drug candidate is in patients who suffer from cirrhosis and high ammonia level in blood with an onset of encephalopathy caused by abnormal liver activity
• Scientific title: Multicenter, Randomized Phase 2B Study to Evaluate the Efficacy, Safety and Tolerability of OCR-002 (ornithine phenylacetate) in Hospitalized Patients with Cirrhosis and Associated, Hyperammonemia with an Episode of Hepatic Encephalopathy - STOP-HE study
• Date of first enrolment: 08/08/2014
• Target sample size: 234
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-005412-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: no Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Bulgaria, Czech Republic, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, Netherlands, Russian Federation, Spain, Ukraine, United Kingdom

Contacts

• Name: Connie Cosentino
• Affiliation: Ocera Therapeutics Inc

• Name: Connie Cosentino
• Affiliation: Ocera Therapeutics Inc

Key inclusion & exclusion criteria

Inclusion criteria:
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 up to 72 hours of hospital diagnosis of HE. There is a special allowance case-by-case with medical monitor review for an extension in this time interval (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 greater than 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).
• 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 156
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 78

Exclusion criteria:
• 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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Hepatic encephalopathy
MedDRA version: 19.0 Level: PT Classification code 10019660 Term: Hepatic encephalopathy System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: ornithine phenylacetate
Product Code: CAS-RN 952154-79-9
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ornithine phenylacetate
CAS Number: 952154-79-9
Current Sponsor code: OCR-002
Other descriptive name: ORNITHINE PHENYLACETATE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: An Independent DMC will conduct a review of safety data monthly for each of the first 3 months of the study, every 2 months for the next 6 months and every 3 months thereafter until study completion (unless no new data); the review will include assessment of survival, an analysis of survival between arms may be performed if 10 or more deaths have occurred. As PK data are generated on a monthly basis, the PK findings of the third party expert pharmacokineticist will be reviewed in conjunction with safety by the Data Monitoring Committee (see above).
An interim analysis of the primary efficacy endpoint will be conducted after the first 37 endpoints are observed to assess the sample size and power of the study, including the impact of censoring due to liver transplant or death.

Main Objective: To evaluate the efficacy of OCR-002 for treatment of an acute hepatic
encephalopathy episode in cirrhotic patients requiring hospitalization
To evaluate the safety and tolerability of OCR-002 in hospitalized
cirrhotic patients with an acute hepatic encephalopathy episode

Primary end point(s): Time to confirmed clinical response (confirmed at next assessment performed or time of first clinical response if occurring at last efficacy evaluation prior to discharge from hospital) defined for patients with Stage 3 (stupor) or 4 (coma) hepatic encephalopathy as a reduction to Stage 2 (see Appendix A), and for patients with Baseline Stage 2 hepatic encephalopathy as improvement to Stage 0/1 (no asterixis and no disorientation based on sentinel 5 questions) using the Hepatic Encephalopathy Staging Tool (Appendix A) after initiation of treatment through 3 hours post end-of-infusion. The Kaplan-Meier (KM) estimate of time to response will be calculated. The difference in the KM median time to response between treatment groups will be used to estimate the decrease in time to improvement obtained through use of study drug. Treatment groups will be compared using a stratified log-rank test (2-sided alpha=0.05). The primary analysis will be stratified by the randomization strata.

The Hepatic Encephalopathy Staging Tool will be assessed twice daily (7 a.m. and 5 p.m. ± 1 hour window) during each infusion day and 3 hours post end-of-infusion for all patients. Other HE parameters (Glasgow Coma Scale, modified orientation log) will be assessed in all patients prior to the start of infusion, and twice daily (7 a.m. and 5 p.m. ± 1 hour window) each infusion day and 3 hours post end-of-infusion. Additionally, a Physician Overall Treatment Evaluation of Hepatic Encephalopathy and Physician Ranked Assessments (specific items) will be performed in the time window between end-of-final infusion and 3 hours post end-of-infusion. Patients remaining in the hospital for standard of care will additionally have HE parameters repeated 24 hours post the end of the final (last) 24-hour infusion and immediately prior to hospital discharge if discharge occurs during the follow-up period. Patients having a liver transplant will be censored at time of transplant. Deaths will be censored at time of death.

Secondary Objective: To confirm the pharmacokinetic (PK) profile of OCR-002 in this patient
population
To assess the kinetics of reduction of plasma ammonia with OCR-002
and excretion of phenylacetylglutamine (PAGN) in urine

Secondary Outcome(s)

Secondary end point(s): Time to confirmed improvement to Stage 0/1 (no asterixis and no disorientation based on sentinel 5 questions) using the Hepatic Encephalopathy Staging Tool (Appendix A) after initiation of treatment through 3 hours post end-of-infusion confirmed at next evaluation performed or time of first clinical response if occurring at last efficacy evaluation prior to discharge from hospital
• Cumulative proportion of patients fulfilling primary endpoint response criteria through 3 hours post end-of-infusion (Hepatic Encephalopathy Staging Tool)
• Change from baseline in the modified orientation log (MO-log)
• Length of stay in hospital from the time of start of study drug infusion until discharge from the hospital
• Length of stay in the ICU from the time of start of study drug infusion for patients in ICU

Timepoint(s) of evaluation of this end point: As for primary endpoint

Secondary ID(s)

2013-005412-10-EE

OCR002-HE209

Source(s) of Monetary Support

Ocera Therapeutics Inc