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    Summary
    EudraCT Number:2013-005412-10
    Sponsor's Protocol Code Number:OCR002-HE209
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-09-16
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2013-005412-10
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.3.2Name or abbreviated title of the trial where available
    STOP-HE study
    A.4.1Sponsor's protocol code numberOCR002-HE209
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOcera Therapeutics Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOcera Therapeutics Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOcera Therapeutics Inc
    B.5.2Functional name of contact pointConnie Cosentino
    B.5.3 Address:
    B.5.3.1Street Address5001 South Miami Blvd., Suite 300
    B.5.3.2Town/ cityDurham
    B.5.3.3Post codeNC 27703
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1919328-1131
    B.5.6E-mailccosentino@ocerainc.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameornithine phenylacetate
    D.3.2Product code CAS-RN 952154-79-9
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNornithine phenylacetate
    D.3.9.1CAS number 952154-79-9
    D.3.9.2Current sponsor codeOCR-002
    D.3.9.3Other descriptive nameORNITHINE PHENYLACETATE
    D.3.9.4EV Substance CodeSUB166528
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInfusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hepatic encephalopathy
    E.1.1.1Medical condition in easily understood language
    Encephalopathy caused by liver failure
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10019660
    E.1.2Term Hepatic encephalopathy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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
    E.2.2Secondary objectives of the trial
    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
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal 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-aspartate and neomycin during study is prohibited.
    • MARS (molecular adsorbent recirculation system) use is prohibited
    • Receiving or will receive sodium benzoate, Ammonul®, sodium phenylbutyrate (Buphenyl®) or glycerol phenylbutyrate (RavictiTM).
    • Participation in another interventional, investigational experimental device or novel drug clinical trial within 30 days prior to admission. Trials of established medications (not for HE) or new techniques must be reviewed case-by-case by the Medical Monitor. Observational studies are allowed.
    • Patient is listed as high priority candidate for liver transplantation ‘Status 1’ per United Network for Organ Sharing (UNOS) definition or for whom the investigator anticipates imminent liver transplantation within 5 days
    • Prior transplant recipient (solid organ, bone marrow, or stem cell)
    • Irreversible brain damage, massive aspiration pneumonia, non-hepatic-encephalopathy causes for altered mental status
    • Known or suspected hypersensitivity or allergic reaction to ornithine (ORN), phenylacetate (PAA), or any of the components of OCR 002
    • Pregnancy or breastfeeding
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    As for primary endpoint
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Belgium
    Bulgaria
    Czech Republic
    Denmark
    Estonia
    France
    Germany
    Hungary
    Israel
    Italy
    Netherlands
    Russian Federation
    Spain
    Ukraine
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 156
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 78
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2014-09-16. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients with acute HE episode defined by Stage ≥ 2 of HET are expected to be enrolled. This condition is associated with impaired cognitive function or unconsciousness, therefore legal representative or close family member will sign ICF
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 234
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-10-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-18
    P. End of Trial
    P.End of Trial StatusCompleted
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