SepsisPhase 4ROCSEPSISNCT02399397

Influence of Age, Sepsis and SLCO1A2 Polymorphisms on Rocuronium Pharmacokinetics

A Phase 4 study testing Serial blood sampling, Train of four monitoring and Blood testing for liver and renal function in people with Sepsis and Systemic Inflammatory Response Syndrome, run by Universidade Estadual Paulista Júlio de Mesquita Filho at 1 site in Brazil.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Sepsis, Systemic Inflammatory Response Syndrome, Septic Shock
What is being tested?: Serial blood sampling, Train of four monitoring and Blood testing for liver and renal function
Type of treatment: Injection or infusion, Surgery or procedure
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 36 participants
Where: 1 siteBrazil
Study dates: Feb 2014to Dec 2015
Phase: Phase 4
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Adult and elderly patients, both gender.
Patients submitted to small to medium-sized surgeries.
Patients who were induced with individual doses of rocuronium, fentanyl and propofol.
Patients with normal renal function (creatinine clearance > 60 mL/min).
Patients with normal liver function.

Who cannot join

Patients who were in use of fluoxetine, carbamazepine, aminoglycoside antibiotics, OATP1A2 inhibitors.
Patients with gastrointestinal and liver diseases, neuromuscular disorders.
Patients who were in chronic use of drugs which alter rocuronium effect.

Trial locations and contacts

1 site in 1 country.

Brazil1 site

Universidade Estadual Paulista Júlio de Mesquita Filho
Araraquara, São Paulo, 14801902

Other trials in Brazil

About this study

Official title: Influence of Sepsis, Age and SLCO1A2 Genetic Polymorphisms on Rocuronium Pharmacokinetics-pharmacodynamics in ASA I-III Surgical Patients

This study aims to evaluate the influence of age and sepsis on in vivo activity of OATP1A2 using rocuronium (ROC) as a probe and evaluating the pharmacokinetics and pharmacodynamics in ASA I-III surgical patients. Thus, adult patients without sepsis (control group, n= 12), adult patients with sepsis (sepsis group, n= 12) and elderly patients without sepsis (elderly group, n= 12), all submitted to small to medium-sized surgeries who were induced with individual doses of rocuronium, fentanyl and propofol are being investigated.

Read the detailed description

Rocuronium (ROC), a neuromuscular blocking agent used in surgical procedures, is primarily eliminated by biliary excretion. Its distribution to the liver, mediated the organic anion transporting polypeptide 1A2 (OATP1A2), is a determining factor for the duration of neuromuscular blockade. Age and release of cytokines during inflammation and infection processes of sepsis can alter expression of SLCO1A2 gene, encoding OATP1A2. The objective of this study is to evaluate the influence of age and sepsis on in vivo activity of OATP1A2 using ROC as a probe and evaluating the pharmacokinetics and pharmacodynamics in ASA I-III surgical patients. Adult patients without sepsis (control group, n=12), adult patients with sepsis (sepsis group, n=12) and elderly patients without sepsis (elderly group, n=12), all submitted to small to medium-sized surgeries are being investigated. All patients are being induced with individual doses of rocuronium, fentanyl and propofol. Serial blood samples are being collected up to 360 minutes after administration of ROC. Neuromuscular blockade induced by ROC is monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same times of blood sampling. The plasma concentration of ROC will be analyzed by liquid chromatography coupled to mass spectrometry with electrospray ionization using positive ion mode.

Conditions: Sepsis, Systemic Inflammatory Response Syndrome, Septic Shock
Being tested: Serial blood sampling, Train of four monitoring, Blood testing for liver and renal function, General anesthesia, Small to medium sized surgery under general anesthesia
Medical subject headings: Sepsis, Systemic Inflammatory Response Syndrome, Shock, Septic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Serial blood samplingProcedure or surgery
Serial blood samples are being collected at times 0, 2, 5, 10, 15, 20, 30, 60, 120, 180, 240 and 360 minutes after rocuronium administration.
Train of four monitoringProcedure or surgery
Also called TOF
Neuromuscular blockade is being evaluated at the same time of blood sampling by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF).
Blood testing for liver and renal functionProcedure or surgery
Blood testing: urea, creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, glycemia
General anesthesiaDrug
Also called Midazolam, Rocuronium, Fentanyl, Propofol
All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol.
Small to medium sized surgery under general anesthesiaProcedure or surgery
Patients classified according American Society of Anesthesiologists (ASA) as ASA I-III and submitted to small-medium sized surgery under general anesthesia were recruited for the present investigation.

Study groups in NCT02399397
Study group	Role	What they receive
Control group	Active comparator	Adult patients(18-50 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase). Receives: Procedure: Serial blood sampling; Procedure: Train of four monitoring; Procedure: Blood testing for liver and renal function; Drug: General anesthesia; Procedure: Small to medium sized surgery under general anesthesia
Sepsis group	Experimental	Adult patients (18-50 years old) ASAII and III with sepsis, systemic inflammatory response syndrome or septic shock submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase). Receives: Procedure: Serial blood sampling; Procedure: Train of four monitoring; Procedure: Blood testing for liver and renal function; Drug: General anesthesia; Procedure: Small to medium sized surgery under general anesthesia
Elderly group	Experimental	Elderly patients (> 65 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase). Receives: Procedure: Serial blood sampling; Procedure: Train of four monitoring; Procedure: Blood testing for liver and renal function; Drug: General anesthesia; Procedure: Small to medium sized surgery under general anesthesia

What is being measured

The primary outcome is the main question the study is designed to answer.

Determination of AUC/dose
Determination of area under the plasma concentration versus time curve (AUC)/dose of rocuronium will be estimated for pharmacokinetic analysis.
Measured: Up to 6h after rocuronium administration

Secondary outcomes (9)

Determination of total clearance
Determination of total clearance of rocuronium will be estimated for pharmacokinetic analysis.
Measured: Up to 6h after rocuronium administration
Determination of volume of distribution
Determination of volume of distribution of rocuronium will be estimated for pharmacokinetic analysis.
Measured: Up to 6h after rocuronium administration
Determination of mean residence time
Determination of mean residence time of rocuronium will be estimated for pharmacokinetic analysis.
Measured: Up to 6h after rocuronium administration
OATP1A2 genotyping using Real Time-PCR
The single nucleotide polymorphisms of SLCO1A2 gene (404A>T, 559G>A, 833delA at coding sequence and -1105G>A, -1032G>A, -715T>C, -361G>A e -189_-188insA at the non-coding sequence of SLCO1A2) are being evaluated in all included patients, using Real Time PCR.
Measured: Up to 5 minutes before rocuronium administration
Analysis of cytokine IL-1α in plasma
Plasma cytokine Interleukin-1α (IL-1α) will be evaluated in each patient.
Measured: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Analysis of cytokine IL-1β in plasma
Plasma cytokine IL-1β will be evaluated in each patient.
Measured: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Analysis of cytokine IL-6 in plasma
Plasma cytokine IL-6 will be evaluated in each patient.
Measured: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Analysis of cytokine TNF-α in plasma
Plasma cytokine Tumor Necrosis Factor-α (TNF-α) will be evaluated in each patient.
Measured: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Pharmacokinetic-Pharmacodynamic analysis: relationship between rocuronium plasma concentration and the neuromuscular blockade
The relationship between rocuronium plasma concentration and the neuromuscular blockade will be described by a sigmoid maximum effect model for each patient
Measured: Up to 6h after rocuronium administration

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Feb 2014Dec 2015

First posted26 Mar 2015 (estimated)
Study startFeb 2014
Primary completionDec 2015
Study completionDec 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (2)Papers the sponsor has linked to this study.
Other trials for SepsisStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 36 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02399397
Sponsor's protocol ID: ROC1314730-0
Acronym: ROCSEPSIS
Status last verified: Oct 2016
First submitted: 2 Mar 2015
Last updated: 25 Jan 2017
Results posted: No
Data monitoring committee: Yes

Publications

de Moraes NV, Lauretti GR, Filgueira GC, Lopes BC, Lanchote VL. Analysis of rocuronium in human plasma by liquid chromatography-tandem mass spectrometry with application in clinical pharmacokinetics. J Pharm Biomed Anal. 2014 Mar;90:180-5. doi: 10.1016/j.jpba.2013.11.032. Epub 2013 Dec 7.
PubMed 24370612
Costa ACC, Coelho EB, Lanchote VL, Correia BV, Abumansur JT, Lauretti GR, de Moraes NV. The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries. Eur J Clin Pharmacol. 2017 Aug;73(8):957-963. doi: 10.1007/s00228-017-2243-1. Epub 2017 Apr 14.
PubMed 28409297

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Sepsis trials

Study at a glance

From the registry record, last updated by the sponsor on 25 Jan 2017. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Influence of Sepsis, Age and SLCO1A2 Genetic Polymorphisms on Rocuronium Pharmacokinetics-pharmacodynamics in ASA I-III Surgical Patients
ClinicalTrials.gov ID: NCT02399397
Acronym / sponsor ID: ROCSEPSIS / ROC1314730-0
Conditions: Sepsis, Systemic Inflammatory Response Syndrome, Septic Shock
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 36 participants (actual)
Lead sponsor: Universidade Estadual Paulista Júlio de Mesquita FilhoUniversity, hospital or other
Collaborators: University of Sao Paulo
Study start: Feb 2014
Primary completion: Dec 2015 (actual)
Study completion: Dec 2015 (actual)
First posted: 26 Mar 2015 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 3

Arm	Type	Receives
Control group	Active comparator	Procedure: Serial blood sampling, Procedure: Train of four monitoring, Procedure: Blood testing for liver and renal function, Drug: General anesthesia, Procedure: Small to medium sized surgery under general anesthesiaAdult patients(18-50 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).
Sepsis group	Experimental	Procedure: Serial blood sampling, Procedure: Train of four monitoring, Procedure: Blood testing for liver and renal function, Drug: General anesthesia, Procedure: Small to medium sized surgery under general anesthesiaAdult patients (18-50 years old) ASAII and III with sepsis, systemic inflammatory response syndrome or septic shock submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).
Elderly group	Experimental	Procedure: Serial blood sampling, Procedure: Train of four monitoring, Procedure: Blood testing for liver and renal function, Drug: General anesthesia, Procedure: Small to medium sized surgery under general anesthesiaElderly patients (> 65 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

Adult and elderly patients, both gender.
Patients submitted to small to medium-sized surgeries.
Patients who were induced with individual doses of rocuronium, fentanyl and propofol.
Patients with normal renal function (creatinine clearance > 60 mL/min).
Patients with normal liver function.

Key exclusion criteria (3 listed)

Patients who were in use of fluoxetine, carbamazepine, aminoglycoside antibiotics, OATP1A2 inhibitors.
Patients with gastrointestinal and liver diseases, neuromuscular disorders.
Patients who were in chronic use of drugs which alter rocuronium effect.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Serial blood samplingSerial blood samples are being collected at times 0, 2, 5, 10, 15, 20, 30, 60, 120, 180, 240 and 360 minutes after rocuronium administration.	Procedure or surgery	Control group, Elderly group, Sepsis group
Train of four monitoringAlso: TOFNeuromuscular blockade is being evaluated at the same time of blood sampling by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF).	Procedure or surgery	Control group, Elderly group, Sepsis group
Blood testing for liver and renal functionBlood testing: urea, creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, glycemia	Procedure or surgery	Control group, Elderly group, Sepsis group
General anesthesiaAlso: Midazolam, Rocuronium, Fentanyl, PropofolAll patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol.	Drug	Control group, Elderly group, Sepsis group
Small to medium sized surgery under general anesthesiaPatients classified according American Society of Anesthesiologists (ASA) as ASA I-III and submitted to small-medium sized surgery under general anesthesia were recruited for the present investigation.	Procedure or surgery	Control group, Elderly group, Sepsis group

Primary outcome

Determination of AUC/dose
Time frame: Up to 6h after rocuronium administration
Determination of area under the plasma concentration versus time curve (AUC)/dose of rocuronium will be estimated for pharmacokinetic analysis.

9 secondary outcomes

Determination of total clearance
Time frame: Up to 6h after rocuronium administration
Determination of volume of distribution
Time frame: Up to 6h after rocuronium administration
Determination of mean residence time
Time frame: Up to 6h after rocuronium administration
OATP1A2 genotyping using Real Time-PCR
Time frame: Up to 5 minutes before rocuronium administration
Analysis of cytokine IL-1α in plasma
Time frame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Analysis of cytokine IL-1β in plasma
Time frame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Analysis of cytokine IL-6 in plasma
Time frame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Analysis of cytokine TNF-α in plasma
Time frame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Pharmacokinetic-Pharmacodynamic analysis: relationship between rocuronium plasma concentration and the neuromuscular blockade
Time frame: Up to 6h after rocuronium administration

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 25 Jan 2017.
Results publication: PubMed 24370612de Moraes NV, Lauretti GR, Filgueira GC, Lopes BC, Lanchote VL. Analysis of rocuronium in human plasma by liquid chromatography-tandem mass spectrometry with application in clinical pharmacokinetics. J Pharm Biomed Anal. 2014 Mar;90:180-5. doi: 10.1016/j.jpba.2013.11.032. Epub 2013 Dec 7.
Derived from this study: PubMed 28409297Costa ACC, Coelho EB, Lanchote VL, Correia BV, Abumansur JT, Lauretti GR, de Moraes NV. The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries. Eur J Clin Pharmacol. 2017 Aug;73(8):957-963. doi: 10.1007/s00228-017-2243-1. Epub 2017 Apr 14.

Related trials for Sepsis

Not yet recruitingPhase 2/3
A Pivotal Safety and Immunogenicity GBS-NN/NN2 Vaccine Maternal Immunisation Trial
Streptococcus Agalactiae Infection, Neonatal Sepsis
Active, not recruiting
CT for Personalized Mechanical Ventilation
Ventilator-Induced Lung Injury, Sepsis Syndrome
RecruitingPhase 4
A Study to Compare the Efficacy and Safety of Extended and Intermittent Infusion of Beta-lactams in Critically Ill Paediatric Patients
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Not yet recruiting
Double Plasma Separation and Adsorption in Acute-on-Chronic Liver Failure (DPMAS-ACLF Trial)
Acute-on-Chronic Liver Failure (ACLF)
Active, not recruitingPhase 4
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Sepsis, Septic Shock

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Natalia V. de Moraes, Prof. principal investigator

Universidade Estadual Paulista Júlio de Mesquita Filho

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Jan 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Determination of AUC/dose (time frame: Up to 6h after rocuronium administration). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02399397, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jan 2017.