Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12610000283077
Ethics application status
Approved
Date submitted
3/03/2010
Date registered
8/04/2010
Date last updated
15/12/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study to evaluate whether increased codeine levels are seen when both codeine and ketamine are given in small doses to well volunteers.
Scientific title
Mechanistic basis for the use of ketamine as an adjuvant to opioid analgesia – a pharmacokinetic drug-drug interaction study to define any clinically relevant drug to drug interaction between codeine and ketamine in healthy volunteers.
Secondary ID [1] 1526 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
The possibility that ketamine,an anaesthetic medication but which is also used at much lower doses, to help try and control severe chronic nerve pain, may increase the effective blood levels of opioids such as codeine or morphine that are often given in conjunction with ketamine. 252339 0
This study is looking at drug metabolism not pain management or anaesthesiology 257109 0
Condition category
Condition code
Other 252530 252530 0 0
Conditions of unknown or disputed aetiology (such as chronic fatigue syndrome/myalgic encephalomyelitis)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study exposure is for 4 days and commences with a comprehensive medical assessment to identify that the participants meet the eligibility criteria.Participants will take in total 9 doses of 30mg of codeine orally every 8 hours. The first 5 doses will be taken at home, ie days 1 and 2 of the study. On day 3 the participants will continue to take the codeine 30mg every 8 hours orally but will be monitored in hospital from 08.00 to 16.00. 11 samples of blood will be taken at predetermined times throughout the day and at the same time vital signs, pulse, respirations and blood pressure, will be measured by a registered nurse. On day 4 the participant will again be monitored in hospital from 08.00 hours to 16.00 hours. The final dose of codeine 30mg orally will be given at 08.00 hours and at the same time ketamine 0.5mg per kg of body weight up to a maximum of 40mg will be given intravenously over 5 minutes. Again 11 blood samples will be taken at predetermined times throughout the day, and vital signs , pulse, respirations and blood pressure will be measured at the same time. An intravenous cannual, a small plastic tube, will be inserted into a vein in the arm on both days 3 and 4 which will be used to collect the 11 blood samples on each day, thus eliminating the need to insert a needle into the vein each time a blood sample is required.
On both days 3 and 4, whilst in hospital, all urine passed by the participants will be collected.
Intervention code [1] 255769 0
Treatment: Drugs
Comparator / control treatment
no treatment
Control group
Uncontrolled

Outcomes
Primary outcome [1] 257547 0
To define any clinically relevant drug to drug interaction between codeine and ketamine in healthy volunteers. This will be measured by taking in total 22 blood sample.
Timepoint [1] 257547 0
At 08.00. 08.30, 09.00, 09.30, 10.00, 11.00, 12.00, 13.00,14.00,15.00 and 16.00 on days 3 and 4 of the study.
Primary outcome [2] 257633 0
This study will allow the relationship between opioid metabolism in the
presence of ketamine to be delineated in a way that can inform
clinical practice if the phase III study is positive.
Timepoint [2] 257633 0
The samples of blood and urine collected will be analysed in the laboratory over the next few months and results should be available within 12 months
Secondary outcome [1] 262790 0
Given that morphine and codeine are metabolised through the same pathways, this study will also inform practice with morphine.
Timepoint [1] 262790 0
The samples of blood and urine collected will be analysed in the laboratory over the next few months and results should be available within 12 months
Secondary outcome [2] 262791 0
Given the almost universal prescribing of ketamine in the presence of an opioid, this study will have wide implications for practice internationally in acute pain including post-operative analgesia, chronic pain and palliative care
Timepoint [2] 262791 0
The samples of blood and urine collected will be analysed in the laboratory over the next few months and results should be available within 12 months

Eligibility
Key inclusion criteria
Participant is capable of completing all participant assessments and complying with the study procedures, is able to give fully informed written consent, Normal performance status = Australian-modified Karnofsky performance stauts of 100.
Minimum age
18 Years
Maximum age
35 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Any history of drug or alcohol abuse, any known allergy to either of the study medications,alcohol consumption during the trial period, on any regular or as needed medications including opioids and Non Steroidal Anti Inflammatory Drugs(NSAIDs),anaemia, renal dysfunction with creatinine clearance calculated as less than 25 ml/minute. Hepatic impairment defined as 2 times upper limit of mormal for 2 or more hepatic enzymes, International normalized ratio (INR >1.2 )– not treated with warfarin, documented respiratory failure induced by any opiate medication,recent seizures or history of uncontrolled epilepsy, medically assessed history of uncontrolled hypertension, cardiac arrhythmias, cardiac failure, ischaemic heart disease or history of cerebral vascular accident, cerebral trauma, intracerebral mass or previous intracerebral haemorrhage, currently taking monoamine oxidase inhibitors (MAOIs) or who have been taking non-reversible monoamine oxidase inhibitors within 4 weeks prior to study entry or reversible MAOIs within 5 days of study entry, history of increased intraocular pressure (e.g. glaucoma), schizophrenia, acute psychosis, acute intermittent porphyria, uncontrolled hyperthyroidism,women pregnant or lactating and if at risk of pregnancy must have appropriate and effective contraception in place.

Study design
Purpose of the study
Treatment
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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
18/11/2009
Actual
21/12/2009
Date of last participant enrolment
Anticipated
5/01/2010
Actual
5/01/2010
Date of last data collection
Anticipated
Actual
Sample size
Target
10
Accrual to date
Final
12
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 256254 0
Charities/Societies/Foundations
Name [1] 256254 0
Foundation Daw Park
Country [1] 256254 0
Australia
Primary sponsor type
University
Name
Flinders University- Department of Clinical Pharmacology
Address
Flinders Medical Centre
Flinders Drive
Bedford Park SA 5042
Country
Australia
Secondary sponsor category [1] 251589 0
University
Name [1] 251589 0
Flinders University Department of Palliative Support Services.
Address [1] 251589 0
700 Goodwood Road
Daw Park SA 5041
Country [1] 251589 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258351 0
Flinders Clinical Research Ethics Committee
Ethics committee address [1] 258351 0
Flinders Medical Centre
Flinders Drive
Bedford Park
SA 5042
Ethics committee country [1] 258351 0
Australia
Date submitted for ethics approval [1] 258351 0
Approval date [1] 258351 0
17/11/2009
Ethics approval number [1] 258351 0
1/09/0324

Summary
Brief summary
Pain from damaged nerves is a common problem particularly in the aged and those with medical problems including diabetes, vascular disease and cancer.A medication called ketamine which is used for anaesthetics is, at much lower doses, also used to help try and control severe chronic nerve pain. In an experiment that has been carried out at Flinders University in the laboratory, it appears that ketamine may increase the effective blood levels of opioid pain killers such as codeine or morphine that are often given in conjunction with ketamine. This study will evaluate whether increased codeine levels are seen when both codeine and ketamine are administered in small doses to well volunteers.Ketamine is already being evaluated in a clinical study by a team led by Flinders University at eight sites across Australia for severe nerve-based pain. This study will be a definitive study on the place of ketamine in the control of chronic, complex pain and should be finished in mid-2010.This study will have huge importance if ketamine is shown to be of clinical benefit. To date, it may well be that the perceived clinical benefit is only because of its effect on increasing the blood levels of strong pain killers.
Trial website
Trial related presentations / publications
N/A
Public notes

Contacts
Principal investigator
Name 30579 0
Prof John Miners
Address 30579 0
Department of Clinical Pharmacology Flinders Medical Centre Flinders Drive Bedford Park SA 5042
Country 30579 0
Australia
Phone 30579 0
+ 61 8 8204 4131
Fax 30579 0
+61 8 8204 5114
Email 30579 0
john.miners@flinders.edu.au
Contact person for public queries
Name 13826 0
Ms Aine Greene
Address 13826 0
Southern Adelaide Paliative Services
700 Goodwood Road
Daw Park SA 5041
Country 13826 0
Australia
Phone 13826 0
+61 8 8275 1057
Fax 13826 0
+61 8 8275 1201
Email 13826 0
aine.greene@health.sa.gov.au
Contact person for scientific queries
Name 4754 0
Professor John Miners
Address 4754 0
Department of Clinical Pharmacology
Flinders Medical Centre
Flinders Drive
Bedford Park SA 5042
Country 4754 0
Australia
Phone 4754 0
+ 61 8 8204 4131
Fax 4754 0
+61 8 8204 5114
Email 4754 0
john.miners@flinders.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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