Clinical Trial Results:
Ensayo clínico aleatorizado y controlado con paracetamol de la seguridad renal de metamizol en el tratamiento de pacientes cirróticos con y sin ascitis (Randomized Controlled Clinical Trial to study the renal safety of acetaminophen vs metamizol in the treatment of cirrotic patients with or without ascitic decompensation)

Trial information Top of page
Trial identification
Sponsor protocol code	UFC-08/01
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Instituto de Salud Carlos III
Sponsor organisation address	C/ Sinesio Delgado, 4 (entrada por Avda. Monforte de Lemos, 5), Madrid, Spain, 28029
Public contact	Pedro Zapater – Hospital General Universitario de Alicante , Hospital General Universitario de Alicante, 34 965913868, zapater_ped@gva.es
Scientific contact	Pedro Zapater – Hospital General Universitario de Alicante , Hospital General Universitario de Alicante, 34 965913868, zapater_ped@gva.es
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	15 Jan 2014
Is this the analysis of the primary completion data?	No
Global end of trial reached?	Yes
Global end of trial date	29 Oct 2010
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To compare the effects of therapeutic doses of dipyrone and acetaminophen used for short periods of time (72 hours) on renal function (glomerular filtration rate evaluated by serum cystatin c) of patients with cirrhosis with or without ascites
Protection of trial subjects	Patients requiring additional analgesic treatment, those developing a serious adverse event or suffering an intercurrent disease that in the opinion of the investigator would compromise patient safety were withdrawn from the study.
Background therapy	Beta-blockers (40% of patients) and diuretics (50% of patients)
Evidence for comparator	Acetaminophen and dipyrone are among the most commonly used analgesic and antipyretic drugs worldwide, either on prescription or on over-the-counter. Case–control studies have shown that acetaminophen was the most common analgesic used by patients with cirrhosis, and this use at therapeutic doses was not associated with an increased risk of being hospitalized for liver-associated events. While acetaminophen is a very weak inhibitor of COX activity, dipyrone may cause a more pronounced decline in prostaglandin synthesis and therefore could be associated with a greater risk of renal damage in patients with cirrhosis in which renal blood flow is dependent on prostaglandin production.
Actual start date of recruitment	12 May 2008
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: 30
Worldwide total number of subjects	30
EEA total number of subjects	30
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)	23
From 65 to 84 years	7
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	The study was performed in patients with cirrhosis without renal injury followed in the Liver Unit of the University General Hospital of Alicante (Spain) that required analgesic or antipyretic treatment from May 2008 to October 2010
Pre-assignment
Screening details	Patients with mild to moderate ascites (ascites grade 1 or 2) were included if they could be treated effectively with medical management. Seven patients were included during an episode of AF decompensation. The 80% of patients in both groups received the study treatment for mild–moderate pain and 20% as antipyretic.
Period 1
Period 1 title	overall trial (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Not blinded
Blinding implementation details	This was an observer-blind study
Arms
Are arms mutually exclusive	Yes
Arm title	Acetaminophen
Arm description	-
Arm type	Active comparator
Investigational medicinal product name	Acetaminophen
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	500 mg t.i.d.
Arm title	Metamizole
Arm description	-
Arm type	Experimental
Investigational medicinal product name	Metamizole
Investigational medicinal product code
Other name	Dipyrone
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	575 mg t.i.d.
Number of subjects in period 1 Acetaminophen Metamizole Started 15 15 Completed 15 14 Not completed 0 1      Adverse event, non-fatal - 1

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Acetaminophen
Reporting group description	-
Reporting group title	Metamizole
Reporting group description	-
Reporting group values Acetaminophen Metamizole Total Number of subjects 15 15 30 Age categorical Units: Subjects     In utero 0 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0 0     Newborns (0-27 days) 0 0 0     Infants and toddlers (28 days-23 months) 0 0 0     Children (2-11 years) 0 0 0     Adolescents (12-17 years) 0 0 0     Adults (18-64 years) 11 12 23     From 65-84 years 4 3 7     85 years and over 0 0 0 Age continuous Units: years     arithmetic mean (standard deviation) 51.8 ± 9.8 56.5 ± 13.5 - Gender categorical Units: Subjects     Female 2 3 5     Male 13 12 25 Cause of cirrhosis Units: Subjects     alcohol 12 13 25     viral 3 2 5 Child-Pugh score Units: arbitrary units     arithmetic mean (standard deviation) 6.7 ± 1.7 7.0 ± 1.5 - Estimated glomerular filtration rate (eGFR) calculated from cystatin C values using the Grubb cystatin C equation. Units: ml/min/(1.73 m2)     arithmetic mean (standard deviation) 77.22 ± 33.39 79.88 ± 51.95 - Serum Cystatin C Units: mg/L     arithmetic mean (standard deviation) 1.2 ± 0.5 1.2 ± 0.6 -

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Acetaminophen
Reporting group description	-
Reporting group title	Metamizole
Reporting group description	-

End points Top of page

Primary: Serum cystatin C at 72 hours Top of page
End point title	Serum cystatin C at 72 hours
End point description
End point type	Primary
End point timeframe	72 hr
End point values Acetaminophen Metamizole Number of subjects analysed 15 14 Units: mg/L     arithmetic mean (standard deviation) 1.2 ± 0.4 1.3 ± 0.5
Statistical analysis title	Differences mean serum cystatin C values at 72 hr
Comparison groups	Acetaminophen v Metamizole
Number of subjects included in analysis	29
Analysis specification	Pre-specified
Analysis type	superiority
P-value	= 0.7
Method	Wilcoxon (Mann-Whitney)
Confidence interval

Primary: Serum cystatin C at 72 hours Top of page

Secondary: Serum cystatin C at 48 hours Top of page
End point title	Serum cystatin C at 48 hours
End point description
End point type	Secondary
End point timeframe	48 hr
End point values Acetaminophen Metamizole Number of subjects analysed 15 15 Units: mg/l     arithmetic mean (standard deviation) 1.3 ± 0.6 1.3 ± 0.6
Statistical analysis title	Differences mean serum cystatin C values at 48 hr
Comparison groups	Acetaminophen v Metamizole
Number of subjects included in analysis	30
Analysis specification	Pre-specified
Analysis type	superiority
P-value	= 0.7
Method	Wilcoxon (Mann-Whitney)
Confidence interval

Secondary: Serum cystatin C at 48 hours Top of page

Secondary: Serum PGE2 at 72 hours Top of page
End point title	Serum PGE2 at 72 hours
End point description
End point type	Secondary
End point timeframe	72 hr
End point values Acetaminophen Metamizole Number of subjects analysed 15 14 Units: pg/mL     median (inter-quartile range (Q1-Q3)) 450 (400 to 500) 700 (550 to 850)
Statistical analysis title	Differences serum PGE2 at 72 hr
Comparison groups	Acetaminophen v Metamizole
Number of subjects included in analysis	29
Analysis specification	Pre-specified
Analysis type	superiority
P-value	< 0.05
Method	Wilcoxon (Mann-Whitney)
Confidence interval

Secondary: Serum PGE2 at 72 hours Top of page

Secondary: PGE2 urine levels at 72 hr Top of page
End point title	PGE2 urine levels at 72 hr
End point description
End point type	Secondary
End point timeframe	72 hr
End point values Acetaminophen Metamizole Number of subjects analysed 15 14 Units: pg/mL     median (inter-quartile range (Q1-Q3)) 500 (200 to 530) 1000 (600 to 1100)
Statistical analysis title	Differences Urine PGE2 at 72 hr
Comparison groups	Acetaminophen v Metamizole
Number of subjects included in analysis	29
Analysis specification	Pre-specified
Analysis type	superiority
P-value	< 0.05
Method	Wilcoxon (Mann-Whitney)
Confidence interval

Secondary: PGE2 urine levels at 72 hr Top of page

Secondary: Serum 6-keto-PGF1 at 72 hr Top of page
End point title	Serum 6-keto-PGF1 at 72 hr
End point description
End point type	Secondary
End point timeframe	72 hr
End point values Acetaminophen Metamizole Number of subjects analysed 15 14 Units: pg/mL     median (inter-quartile range (Q1-Q3)) 150 (125 to 160) 300 (250 to 450)
Statistical analysis title	Differences serum 6-keto-PGF1 at 72 hr
Comparison groups	Acetaminophen v Metamizole
Number of subjects included in analysis	29
Analysis specification	Pre-specified
Analysis type	superiority
P-value	< 0.05
Method	Wilcoxon (Mann-Whitney)
Confidence interval

Secondary: Serum 6-keto-PGF1 at 72 hr Top of page

Secondary: Urine 6-keto-PGF1 at 72 hr Top of page
End point title	Urine 6-keto-PGF1 at 72 hr
End point description
End point type	Secondary
End point timeframe	72 hr
End point values Acetaminophen Metamizole Number of subjects analysed 15 14 Units: pg/mL     median (inter-quartile range (Q1-Q3)) 750 (550 to 900) 1350 (1150 to 1400)
Statistical analysis title	Differences urine 6-keto-PGF1 at 72 hr
Comparison groups	Acetaminophen v Metamizole
Number of subjects included in analysis	29
Analysis specification	Pre-specified
Analysis type	superiority
P-value	< 0.05
Method	Wilcoxon (Mann-Whitney)
Confidence interval

Secondary: Urine 6-keto-PGF1 at 72 hr Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	adverse events were recorded during the 72 hours of oral administration treatment and until 7 days after end drug administration
Assessment type	Non-systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	2019AB
Reporting groups
Reporting group title	Acetaminophen
Reporting group description	-
Reporting group title	Metamizole
Reporting group description	-
Serious adverse events Acetaminophen Metamizole Total subjects affected by serious adverse events      subjects affected / exposed 0 / 15 (0.00%) 1 / 15 (6.67%)      number of deaths (all causes) 0 0      number of deaths resulting from adverse events 0 0 Hepatobiliary disorders Ascites Additional description: One patient treated with dipyrone required a large-volume paracentesis (6.5 l) 24 hr after inclusion      subjects affected / exposed 0 / 15 (0.00%) 1 / 15 (6.67%)      occurrences causally related to treatment / all 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 0%
Non-serious adverse events Acetaminophen Metamizole Total subjects affected by non serious adverse events      subjects affected / exposed 1 / 15 (6.67%) 2 / 15 (13.33%) Renal and urinary disorders Haematuria      subjects affected / exposed 1 / 15 (6.67%) 2 / 15 (13.33%)      occurrences all number 1 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.
Finally, it was not possible to recruit the number of patients initially expected of 40 necessary to analyze differences based on the presence or absence of ascites between the two treatments.
Online references
http://www.ncbi.nlm.nih.gov/pubmed/25154757

More information Top of page