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Trial registered on ANZCTR


Registration number
ACTRN12620001039976
Ethics application status
Approved
Date submitted
16/07/2020
Date registered
13/10/2020
Date last updated
13/10/2020
Date data sharing statement initially provided
13/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparing blood concentrations of intravenous and nebulized sedatives and analgesics in patients who are on mechanical ventilation.
Scientific title
The PISA Study
Comparative plasma Pharmacokinetics of Intravenous and nebulized Sedatives and Analgesic agents in mechanically ventilated patients: a prospective study.
Secondary ID [1] 301118 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
The PISA Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Comparative plasma pharmacokinetics and bioavailability between intravenous and nebulized route of drug (sedative and analgesic) delivery 318176 0
Condition category
Condition code
Anaesthesiology 316190 316190 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a single site, cross-over study, comparing the plasma pharmacokinetics (PK)s of sedative and analgesic agents with two routes of drug administration in critical care mechanically ventilated patients. In this study 60 patients who meet the inclusion criteria and none of the exclusion criteria will be recruited. In addition to the standard analgesia and sedation prescribed by the treating clinician, each patient will be assigned up to two drugs of investigation at any given time. The drug selection will depend on the following factors:
• Exclusion of drugs with known hypersensitivity in the patient.
• Exclusion of drugs that patient is already receiving as therapy via any route or frequency.

Approach toward selecting study drug will include-
1. Inclusion criteria includes “requiring sedation and or analgesia as per treating team” – high likelihood of receiving at least one of the drugs being tested
2. Drugs that are being administered to the patients will be excluded. For e.g. if the patient is on fentanyl infusion, then fentanyl will not be a study drug.
3. Exclude drugs with known hypersensitivity in the patient e.g. if patient is allergic to morphine then morphine will not be a study drug.
4. May exclude drugs with synergistic effect- eg. if increased risk of hypotension –Dexmedetomidine and Clonidine would preferably not be used together
5. Selection of drug/drugs based on meeting recruitment target for drugs (10 complete sets for each drug – nebulised and Intravenous route)

Each drug will be serially administered via one route Intravenous (IV) /nebulised (NEB) and after a minimum washout period of 12 hours following the sampling time, the 2nd route of administration. When enrolment is for two drugs, these will be administered via different routes. For example, if recruited for fentanyl and midazolam, then if fentanyl is administered intravenously, midazolam will be given concurrently via nebulized route initially with the administration routes changed to nebulization and intravenous respectively in the subsequent stage. The initial method of administration for each drug will be determined by a flip of a coin.

Based on data from existing studies, the study drugs and their doses according to the route of administration include:

Drugs (same for intravenous and nebulized route)

Sedative agents
Midazolam 5 mg
Clonidine 75 µg
Dexmedetomidine 50 µg

Analgesic agents
Fentanyl 50 µg
Morphine 5 mg
Ketamine 25 mg

Intravenous drug administration:
Participants will be administered the study drug intravenously via an existing peripheral or central intravenous catheter as per ICU policy and practise.

Nebulized administration:
A disposable vibrating mesh nebulizer that is currently being used in ICU will be utilised for the nebulization of the study drug. As per current practice, the nebulizer will be placed in the inspiratory limb of the circuit before the Y-piece. If there is a nebulizer in the circuit, only the nebulizer chamber will be replaced and the T-piece will not be changed. The study drugs will be diluted with normal saline. This solution will be instilled in the nebulizer reservoir.

Blood samples will be collected over six hours from an existing arterial line or central venous catheter into heparinised tubes. A urine creatinine clearance will be performed over the sampling period up to 8 hour poste commencement of drug and a sample will be kept to determine drug renal excretion.

Monitoring fidelity: Protocol adherence will be easily monitored as this is a single site study and the study team will be directly involved in each case. The study will be conducted in accordance with ethical principles consistent with the Declaration of Helsinki, and all relevant national and local guidelines on the ethical conduct of research. The research team will include experienced research coordinators, intensive care specialists as all with GCP training and they will have oversight of all study required activities and protocol adherence.

All data will be entered directly from the source in to the electronic database. The data base has the capacity to run validity checks and logic queries to minimise errors. De-identified sampling spread sheets uploaded to the data base for validation of sampling time points. Audit of 100% consent, source data verification of essential data points for 20 % of participants.
Intervention code [1] 318316 0
Treatment: Drugs
Intervention code [2] 318317 0
Treatment: Devices
Comparator / control treatment
This is a cross-over study, comparing the plasma PKs of sedative and analgesic agents with two routes of drug administration in critical care mechanically ventilated patients. Each patient will be their own control as they will each receive both an intravenous and a nebulized dose of the same drug.

For the purpose of this study the IV administration method will be referenced as the comparator.
Control group
Active

Outcomes
Primary outcome [1] 324374 0
Comparative PK between nebulized and intravenous sedatives and analgesics.
Method of assessment- using blood and urine samples

The plasma samples will be analysed using a validated high-performance liquid chromatography (HPLC) method on a Nexera2 UHPLC system coupled to a 8050 triple quadruple mass spectrometer (Shimadzu Corporation, Kyoto, Japan). Bioanalysis will be conducted in accordance with U.S.A FDA guidance for industry on bioanalysis. at the Central Bioanalysis Laboratory at the University of Queensland.

The following Pk parameters will be examined- area under the concentration–time curve extrapolated to infinity (AUC(0–8)), peak plasma concentration (Cmax,), the time to reach Cmax (Tmax), and the mean residence time (MRT (0–t)), the terminal half-life (T1/2) and the clearance rate (CL) will be obtained. The absolute bioavailability will be calculated by F=(AUC inhalation×Dose i.v.)/(AUC i.v.×dose inhalation)×100%
Timepoint [1] 324374 0
Plasma samples will be collected over six hours (T+5, +10, +15, +30, +60, +90, +120, +180, +240 and +360 minutes) from an existing arterial line or central venous catheter for each delivery method.
Primary outcome [2] 324747 0
Creatinine Clearance 8-hour creatinine clearance collected on the sampling days. This will be analysed by the Queensland Pathology laboratory
Timepoint [2] 324747 0
Creatinine clearance will be measured once at the end of the 8 hour urine collection period collected on the sampling days
Primary outcome [3] 325085 0
Renal excretion of study drug from the total volume urine sample collected over dosing interval- analysed by the UQCCR Bioanalysis laboratory
Timepoint [3] 325085 0
A 1 mL sample will be collected from total volume at the end of the 8 hour urine collection
Secondary outcome [1] 384489 0
Secondary study objectives are to evaluate the immediate adverse effects on airway and lungs.

Participants will be observed for the following adverse effects
• Bronchospasm
• Hypoxia
• Patient-ventilator dyssynchrony
Participants will be observed for adverse effects by the treating team, nursing and medical and the research team the medical and nursing who perform the study related procedures
Timepoint [1] 384489 0
Adverse effects on the airway and lungs will be observed during and up to 24 hours after sampling occasions.

Eligibility
Key inclusion criteria
A mechanically ventilated patient requiring sedation and or analgesia who meets all the inclusion criteria and none of the exclusion criteria will be considered for study participation.

Inclusion criteria
1. Adult (>/= 18 years) ICU patient
2. Patient is receiving mechanical ventilation, FiO2< /= 40%, PEEP< /= 10 cm H20.
3. Patient has arterial line or central venous line for blood sampling
4. Patient requiring sedation and or analgesia as per the treating team.
5. Informed consent to participate in the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria
1. Suspected or known hypersensitivity to the drug being studied.
2. Severe chronic lung disease e.g. severe chronic airways disease, lung cancer
3. High ventilatory requirement. For e.g. FiO2>/=40% and PEEP >/=10 cm H20
4. Receiving extra-corporeal membrane oxygenation
5. Receiving renal replacement therapy
6. Liver failure or Child-Pugh C liver cirrhosis
7. Pregnant patients or lactating mothers

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Power calculation and sample size
Whilst it is not possible to perform a sample size calculation for an observational PK modelling study because there is no intervention applied, a minimum of 10 participants will be recruited for each study drug - based on data from similar studies. This sample size will provide a power of 80% (assuming an a of 0.05 and r2 of 30%) and is expected to obtain robust population PK parameter predictions in this patient population, which demonstrates high PK variability.

In their study, Tam et al., demonstrated that with a sample size of 10, the bias and precision of PK predictions were <25% (predictions were considered acceptable if bias/precision for the mean and variability of PK parameters were <25%)

Pharmacometric analysis plan

Primary PK parameters will be calculated using a non-compartmental PK analysis. An attempt will be made to correlate any differences in these primary PK parameters between patients, with clinical and demographic characteristics of the patient. Equivalent nebulization dose compared to the intravenous dose will be computed so as to inform future clinical trials.

The plasma samples will be collected and analysed for the drug concentrations using a validated high-performance liquid chromatography (HPLC) method on a Nexera2 UHPLC system coupled to a 8050 triple quadruple mass spectrometer (Shimadzu Corporation, Kyoto, Japan). Bioanalysis will be conducted in accordance with U.S.A FDA guidance for industry on bioanalysis at the Central Bioanalysis Laboratory at the University of Queensland.


Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
9/11/2020
Actual
Date of last participant enrolment
Anticipated
30/09/2023
Actual
Date of last data collection
Anticipated
31/10/2023
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 30711 0
4029 - Royal Brisbane Hospital

Funding & Sponsors
Funding source category [1] 305562 0
Other Collaborative groups
Name [1] 305562 0
Metro North Hospitals and Health Service - University of Queensland Collaborative Reserach Grant
Country [1] 305562 0
Australia
Funding source category [2] 306159 0
Charities/Societies/Foundations
Name [2] 306159 0
Royal Brisbane and Women's Hospital Foundation Research Grant
Country [2] 306159 0
Australia
Funding source category [3] 306160 0
Hospital
Name [3] 306160 0
Metro North Hospital and Health Services Fellowship Grant
Country [3] 306160 0
Australia
Primary sponsor type
University
Name
REDUCE Centre for Research Excellence - University of Queensland
Address
UQCCR
The University of Queensland
Royal Brisbane and Women's Hospital
Butterfield Street,
Herston Queensland 4029 Australia
Country
Australia
Secondary sponsor category [1] 306630 0
None
Name [1] 306630 0
Address [1] 306630 0
Country [1] 306630 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305868 0
Royal Brisbane and Women's Hospital Ethics Committee
Ethics committee address [1] 305868 0
Royal Brisbane and Women's Hospital
Butterfield Street
Herston Queensland 4029
Ethics committee country [1] 305868 0
Australia
Date submitted for ethics approval [1] 305868 0
07/05/2020
Approval date [1] 305868 0
10/06/2020
Ethics approval number [1] 305868 0
HREC/2020/QRBW/64090:

Summary
Brief summary
Pain and discomfort are commonly associated with all disease conditions especially in critical care. Despite pharmacological developments, the management of pain and discomfort remains suboptimal and often associated with complications. Administering the existing drugs via the inhaled route could achieve better concentration of the drug for effective pain relief and sedation while avoiding side effects. Previous studies have demonstrated safety and often efficacy of inhaled sedatives and pain relief. However, due to the absence of concentration data there is lack of dosing guidelines and hence leading to variable dosing which causes inadequate clinical effect.

This is a prospective, open labelled observational Pharmacokinetic (PK) (drug metabolism) study with the aim of describing the comparative concentrations of the single dose sedatives and pain relief agents between intravenous, through the vein and inhaled routes of drug delivery. Blood and urine samples will be studied to assess the concentrations of the sedative and pain relief. The following drugs will be observed: fentanyl, morphine, midazolam, clonidine, dexmedetomidine and ketamine.

It is hoped that the knowledge gained from this study will enable the development of dosing regimens for optimal inhaled sedative and pain relief therapy.

We plan to recruit at least 10 participants per drug for this study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101870 0
Dr Jayesh Dhanani
Address 101870 0
Department of Intensive Care Medicine,
Royal Brisbane and Women’s Hospital,
Butterfield Street
Herston QLD 4029
Country 101870 0
Australia
Phone 101870 0
+61 7 3646 8897
Fax 101870 0
Email 101870 0
[email protected]
Contact person for public queries
Name 101871 0
Jayesh Dhanani
Address 101871 0
Department of Intensive Care Medicine,
Royal Brisbane and Women’s Hospital,
Butterfield Street
Herston QLD 4029
Country 101871 0
Australia
Phone 101871 0
+61 7 3646 8897
Fax 101871 0
Email 101871 0
[email protected]
Contact person for scientific queries
Name 101872 0
Jayesh Dhanani
Address 101872 0
Department of Intensive Care Medicine,
Royal Brisbane and Women’s Hospital,
Butterfield Street
Herston QLD 4029
Country 101872 0
Australia
Phone 101872 0
+61 7 3646 8897
Fax 101872 0
Email 101872 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
8439Study protocol    379703-(Uploaded-16-07-2020-16-23-49)-Study-related document.pdf
8440Ethical approval    379703-(Uploaded-16-07-2020-16-24-17)-Study-related document.pdf



Results publications and other study-related documents

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