Clinical Trial Results:
Efectos de la administración de ornitina-fenilacetato (OCR-002) en pacientes con cirrosis y hemorragia digestiva alta. Effects of the administration of ornithine phenylacetate (OP, OCR-002) in patients with cirrhosis and upper gastrointestinal bleeding

Trial information Top of page
Trial identification
Sponsor protocol code	OP-GIB
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	VHIR
Sponsor organisation address	Passeig Vall Hebron 119-129, Barcelona, Spain, 08035
Public contact	Joaquin Lopez-Soriano, VHIR, joaquin.lopez.soriano@vhir.org
Scientific contact	Juan Cordoba, VHIR, jcordoba@vhebron.net
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	24 Mar 2015
Is this the analysis of the primary completion data?	Yes
Primary completion date	24 Mar 2015
Global end of trial reached?	Yes
Global end of trial date	24 Mar 2015
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	Evaluar la eficacia del fármaco experimental para reducir la concentración plasmática de amoníaco que sigue a una hemorragia digestiva en pacientes con cirrosis hepática
Protection of trial subjects	Patients were admitted to a semi-intensive care unit (Bleeding Unit) for at least 48 hours, until clinical stability was established. After this period of time, patients were transferred to a general medicine ward.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	03 Oct 2011
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Spain: 38
Worldwide total number of subjects	38
EEA total number of subjects	38
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	38
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	-
Pre-assignment
Screening details	-
Pre-assignment period milestones
Number of subjects started	38
Number of subjects completed	38
Period 1
Period 1 title	Overall trial (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Carer, Assessor
Arms
Are arms mutually exclusive	Yes
Arm title	Ornithine
Arm description	-
Arm type	Experimental
Investigational medicinal product name	Ornithine Phenilacetate
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	Administration of OP (OCR-002) during 5 days in addition to standard treatment of gastrointestinal bleeding
Arm title	Placebo
Arm description	-
Arm type	Placebo
Investigational medicinal product name	Saline 0.9%
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	Administration of control infusion (saline infusion) during 5 days in addition to standard treatment of gastrointestinal bleeding.
Number of subjects in period 1 Ornithine Placebo Started 18 20 Completed 18 20

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Overall trial
Reporting group description	-
Reporting group values Overall trial Total Number of subjects 38 38 Age categorical Units: Subjects     In utero 0     Preterm newborn infants (gestational age < 37 wks) 0     Newborns (0-27 days) 0     Infants and toddlers (28 days-23 months) 0     Children (2-11 years) 0     Adolescents (12-17 years) 0     Adults (18-64 years) 0     From 65-84 years 0     85 years and over 0 Age continuous Units: years     median (standard deviation) 56 ± 11 - Gender categorical Units: Subjects     Female 12 12     Male 26 26

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Ornithine
Reporting group description	-
Reporting group title	Placebo
Reporting group description	-

End points Top of page

Primary: Decrease Ammonium in plasma Top of page
End point title	Decrease Ammonium in plasma
End point description	The primary outcome was a decrease in average venous plasma ammonia at 24 hours. Ammonia was measured in a Cobas 6000 analyzer (Roche Diagnostics Indianapolis, IN, USA) by standard methodology.
End point type	Primary
End point timeframe	24 hours
End point values Ornithine Placebo Number of subjects analysed 18 20 Units: micromole(s)/litre     median (confidence interval 5%) -20.40 (-39.20 to -2.80) -11.88 (-36.75 to -2.35)
Statistical analysis title	Ammonia levels plasma
Comparison groups	Ornithine v Placebo
Number of subjects included in analysis	38
Analysis specification	Pre-specified
Analysis type	superiority
P-value	> 0.05
Method	Wilcoxon (Mann-Whitney)
Parameter type	Mean difference (final values)
Confidence interval

Primary: Decrease Ammonium in plasma Top of page

Secondary: Plasma Phenylacetate 120h Top of page
End point title	Plasma Phenylacetate 120h
End point description
End point type	Secondary
End point timeframe	120 hours
End point values Ornithine Placebo Number of subjects analysed 18 20 Units: micromole(s)/litre     arithmetic mean (standard deviation) 110.5 ± 131.4 1.1 ± 1.8
Statistical analysis title	Phenylacetate plasma
Comparison groups	Placebo v Ornithine
Number of subjects included in analysis	38
Analysis specification	Pre-specified
Analysis type	superiority
P-value	< 0.05
Method	t-test, 2-sided
Confidence interval

Secondary: Plasma Phenylacetate 120h Top of page

Secondary: PAGN urine Top of page
End point title	PAGN urine
End point description	Accumulated mmol in urine at 120 hours
End point type	Secondary
End point timeframe	120 hours
End point values Ornithine Placebo Number of subjects analysed 18 20 Units: micromole(s)/litre     arithmetic mean (standard deviation) 190 ± 85 9.5 ± 9.8
Statistical analysis title	Accumulated PAGN urine
Comparison groups	Ornithine v Placebo
Number of subjects included in analysis	38
Analysis specification	Pre-specified
Analysis type	superiority
P-value	< 0.05
Method	t-test, 1-sided
Confidence interval

Secondary: PAGN urine Top of page

Secondary: PAGN/Creatinine urine Top of page
End point title	PAGN/Creatinine urine
End point description
End point type	Secondary
End point timeframe	120 hours
End point values Ornithine Placebo Number of subjects analysed 18 20 Units: mmol/mol     arithmetic mean (standard deviation) 3177 ± 1400 178 ± 232
Statistical analysis title	PAGN/Creatinine in urine
Comparison groups	Ornithine v Placebo
Number of subjects included in analysis	38
Analysis specification	Pre-specified
Analysis type	superiority
P-value	< 0.05
Method	t-test, 1-sided
Confidence interval

Secondary: PAGN/Creatinine urine Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	All the study
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	14.1
Reporting groups
Reporting group title	Total adverse events
Reporting group description	-
Serious adverse events Total adverse events Total subjects affected by serious adverse events      subjects affected / exposed 10 / 38 (26.32%)      number of deaths (all causes) 0      number of deaths resulting from adverse events 0 Nervous system disorders Seizure      subjects affected / exposed 1 / 38 (2.63%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Subdural haematoma      subjects affected / exposed 1 / 38 (2.63%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Blood and lymphatic system disorders Hemorrhagic shock      subjects affected / exposed 1 / 38 (2.63%)      occurrences causally related to treatment / all 1 / 1      deaths causally related to treatment / all 0 / 0 Neutropenia      subjects affected / exposed 1 / 38 (2.63%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Gastrointestinal disorders Upper gastrointestinal haemorrhage      subjects affected / exposed 3 / 38 (7.89%)      occurrences causally related to treatment / all 0 / 3      deaths causally related to treatment / all 0 / 0 Hepatobiliary disorders Hepatic encephalopathy      subjects affected / exposed 1 / 38 (2.63%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Respiratory, thoracic and mediastinal disorders Respiratory tract infection      subjects affected / exposed 2 / 38 (5.26%)      occurrences causally related to treatment / all 0 / 2      deaths causally related to treatment / all 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Total adverse events Total subjects affected by non serious adverse events      subjects affected / exposed 19 / 38 (50.00%) Vascular disorders Edema      subjects affected / exposed 3 / 38 (7.89%)      occurrences all number 3 Nervous system disorders Dizziness      subjects affected / exposed 2 / 38 (5.26%)      occurrences all number 2 Anxiety      subjects affected / exposed 2 / 38 (5.26%)      occurrences all number 2 Blood and lymphatic system disorders Leukopenia      subjects affected / exposed 3 / 38 (7.89%)      occurrences all number 3 Lymphopenia      subjects affected / exposed 3 / 38 (7.89%)      occurrences all number 3 Neutropenia      subjects affected / exposed 4 / 38 (10.53%)      occurrences all number 4 Hypertension      subjects affected / exposed 2 / 38 (5.26%)      occurrences all number 2 General disorders and administration site conditions Pyrexia      subjects affected / exposed 9 / 38 (23.68%)      occurrences all number 9 Gastrointestinal disorders Abdominal pain      subjects affected / exposed 4 / 38 (10.53%)      occurrences all number 4 Diarrhoea      subjects affected / exposed 3 / 38 (7.89%)      occurrences all number 3 Nausea      subjects affected / exposed 2 / 38 (5.26%)      occurrences all number 2 Hepatobiliary disorders Ascites      subjects affected / exposed 2 / 38 (5.26%)      occurrences all number 2 Musculoskeletal and connective tissue disorders Cramps      subjects affected / exposed 2 / 38 (5.26%)      occurrences all number 2 Metabolism and nutrition disorders Hypokalaemia      subjects affected / exposed 10 / 38 (26.32%)      occurrences all number 10 Hyponatraemia      subjects affected / exposed 5 / 38 (13.16%)      occurrences all number 5 Alkaline Phosphatase increased      subjects affected / exposed 2 / 38 (5.26%)      occurrences all number 2 Hyperglycaemia      subjects affected / exposed 13 / 38 (34.21%)      occurrences all number 13 Asthenia      subjects affected / exposed 3 / 38 (7.89%)      occurrences all number 3 Hypocalcaemia      subjects affected / exposed 2 / 38 (5.26%)      occurrences all number 2

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? No
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
The current study did not achieve the primary objective, probably due to individual variability, a small number of patients included and mainly, too low a dose of OP administered.
Online references
http://www.ncbi.nlm.nih.gov/pubmed/27803737

More information Top of page