Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12619000108112p
Ethics application status
Submitted, not yet approved
Date submitted
30/11/2018
Date registered
24/01/2019
Date last updated
24/01/2019
Date data sharing statement initially provided
24/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Prospective, double-blind, randomised study of the efficacy of ketamine for oropharyngeal mucositis pain
Scientific title
Prospective, double-blind, randomised study of the efficacy of ketamine for oropharyngeal mucositis pain
Secondary ID [1] 296543 0
ERM Project ID: 44541
Monash Health Ref: RES-18-0000516A
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer treatment-related oropharyngeal mucositis pain 310325 0
Condition category
Condition code
Cancer 309056 309056 0 0
Any cancer
Oral and Gastrointestinal 309057 309057 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Skin 309409 309409 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The purpose of the proposed study is to determine the effectiveness of ketamine, for managing cancer treatment-related (chemotherapy, radiotherapy, targeted therapy, immunotherapy, or haematological treatments) oropharyngeal mucositis pain.

This prospective, double-blind, randomised study will see participants randomised to one of two study arms;
1. Intervention Arm: Continuous subcutaneous infusion (CSCI) of ketamine with 5mg midazolam.
The dosing schema is as follows;
Day 1: 100mg ketamine with 5mg midazolam via CSCI over 24 hours.
If pain remains uncontrolled then the dose is escalated to;
Day 2: 200mg ketamine with 5mg midazolam via CSCI over 24 hours.
If pain remains uncontrolled then the dose is escalated to;
Day 3: 300mg ketamine wih 5mg midazolam via CSCI over 24 hours.
The ketamine infusion is maintained at the effective or maximal dose for 72 hours.

2: Active Control: 5mg midazolam via CSCI over 24 hours.

The effectiveness of the intervention will be assessed by;
? Clinically improvement in average pain of >/= 2 Brief Pain Inventory (BPI: Appendix A) units in the absence of more than four breakthrough doses of analgesia over the previous 24 hours.
? Analgesic requirements reduction of 50% or greater in 24-hour opioid dose, or a 50% or greater reduction in the number of opioid breakthrough doses.
? Improvement in oral intake at the end of the 5-day study period.
Intervention code [1] 312848 0
Treatment: Drugs
Comparator / control treatment
This prospective, double-blind, randomised study will see participants randomised to one of two study arms;
1. Intervention Arm: Continuous subcutaneous infusion (CSCI) of ketamine with 5mg midazolam.

2 Active Control: 2: 5mg midazolam via CSCI over 24 hours.
The dosing schema is as follows;
Day 1: 5mg midazolam via CSCI over 24 hours.
If pain remains uncontrolled then the dose is escalated to;
Day 2: 5mg midazolam via CSCI over 24 hours.
If pain remains uncontrolled then the dose is escalated to;
Day 3: 5mg midazolam via CSCI over 24 hours.
The infusion is maintained at the effective or maximal dose for 72 hours.

The effectiveness of the intervention will be assessed by;
? Clinically improvement in average pain of >/= 2 Brief Pain Inventory (BPI: Appendix A) units in the absence of more than four breakthrough doses of analgesia over the previous 24 hours.
? Analgesic requirements reduction of 50% or greater in 24-hour opioid dose, or a 50% or greater reduction in the number of opioid breakthrough doses.
? Improvement in oral intake at the end of the 5-day study period.
Control group
Active

Outcomes
Primary outcome [1] 308019 0
NB: Composite Primary Outcome

To measure the effectiveness of ketamine in the treatment of oropharyngeal mucositis pain,

The effectiveness of ketamine in treating oropharyngeal mucositis pain will be assessed across three domains;

1. Change in patient-reported levels of pain as assessed by the Brief Pain Inventory (BPI) in the absence of more than four breakthrough doses of analgesia over the previous 24 hours. A significant change is considered a change of 2 or more BPI units.

2. Change in analgesic requirements, in particular 24-hour opioid dose and number of opioid breakthrough doses.

3. Change in oral intake at the end of the 5-day study period.
Timepoint [1] 308019 0
The timepoints at which the effectiveness of ketamine in treating oropharyngeal pain will be assessed is as follows;
1. The Brief Pain Inventory (BPI) will be completed once per day of a patient's engagement (up to 5 days) with the project and will be administered by research staff.
2. Continued monitoring of analgesic requirements will occur for the duration of the trial to ensure that a patient's analgesia needs are being met. Retrospective analysis of nursing notes, by way of analysis of medical records, will look to affirm a correlation between ketamine and a reduction in analgesic requirements for the duration of a patient's engagement (up to 5 days)..
3. Retrospective analysis of medical notes will look for a correlation between ketamine and oral intake for the duration of a patient's engagement (up to 5 days).

Primary outcome [2] 308020 0
Metabolism of ketamine assessed using serum assay.
Timepoint [2] 308020 0
After about 18 hours at each dose level a 7 ml blood sample will be taken; 2 ml will be place in an EDTA tube and stored frozen for subsequent genotyping; 5 ml will be centrifuged, and the plasma will be frozen for subsequent plasma concentration analysis.
Plasma samples will be assayed for R- and S-ketamine and R and S-norketamine by an LC/MS/MS method.
Primary outcome [3] 308021 0
NB: Composite Primary Outcome

To test isolated DNA for specific genetic variants (NMDA, AMPA, BDNF and innate immune markers IL6 and TNF) that affect ketamine’s metabolising enzymes and brain receptors.
Timepoint [3] 308021 0
After about 18 hours at each dose level a 7 ml blood sample will be taken; 5 ml will be centrifuged, and the plasma will be frozen for subsequent plasma concentration analysis.
The genotyping data will be described in terms of allele frequency and genotyping frequency and will be evaluted to ensure they conform to the Hardy-Weinberg Equilibrium.
Secondary outcome [1] 353664 0
Mood assessed using;
- Hamilton Rating Scale for Depression
- Becks Depression Index - Second Edition
- Hospital Anxiety and Depression Scale
Timepoint [1] 353664 0
Mood will be assessed once per day of a patient's engagement (up to 5 days) with the project and will be administered by research staff.
Secondary outcome [2] 353665 0
Adverse events assessed using;
- National Institute of Health Common Terminology Criteria for Adverse Events
- Clinician-Administered Dissociative States Scale
Timepoint [2] 353665 0
Any adverse events (for example; tachycardia, nausea or vomiting) and psychomimetic-specific events (for example, psychological manifestations varying from pleasant dream-like state to delirium) .will be recorded and graded daily for the duration of a patient's participation (up to 5 days)

Eligibility
Key inclusion criteria
Patient Inclusion Criteria:
• Treatment related oral or pharyngeal mucositis with average pain score of >/= 4 on the Brief Pain Inventory (BPI)
• Males and females aged over 18 years.
• Able to provide informed consent and complete questionnaires.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patient Exclusion Criteria:

• Patients in who significant hypertension or tachycardia would be potentially dangerous.
• Patients who have previously received ketamine for chronic pain by any route of administration prior to the study within the preceding six months will be excluded. Patients who have received ketamine for an anaesthetic indication, will not be excluded.
• Patients who have undergone any other procedure or therapy likely to affect pain during the study period.
• Patients with recent seizures or a history of uncontrolled epilepsy not related to the underlying malignancy.
• Patients with a documented history of uncontrolled hypertension, cardiac arrhythmias, cardiac failure, ischaemic heart disease or recent history of cerebral vascular accident, cerebral trauma, intracerebral mass or haemorrhage.
• Patients with a documented history of increased intraocular pressure such as glaucoma.
• Patients with a known serious psychiatric illness such as schizophrenia, acute psychosis excluding depression and anxiety.
• Patients with a documented history of acute intermittent porphyria.
• Patients with a documented history of uncontrolled hyperthyroidism. (Patients receiving thyroid replacement must have a thyroid stimulating hormone (TSH) serum level within the normal range).
• Patients currently taking prohibited drugs such as rifampicin, carbamazepine, phenytoin and diazepam.
• Patients 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 2 days of study entry.
• Patients who have participated in a clinical study of a new chemical entity within the last month, prior to study entry.
• Any patient who has had an adverse reaction to ketamine in the past.
• Comorbidities contraindicating the use of ketamine.
• Severe organ dysfunction.
• Pregnancy and lactation.
• All participants are required to use an effective form of contraception.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment will be maintained by the delegation of randomisation to pharmacy staff.

Pharmacy staff will dispense the agent (either interventional or active control) such that administering staff, the patient and research staff will be blinded to it's contents.

Pharmacy staff will retain a log of randomisation profiles until such a time that unblinding will occur.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will occur on a 1:1 basis using a random letter table generated by STATA software. Random block sizes will be used.

Patients will be stratified according to their site of recruitment.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
To show a different of at least 2 points in mean score of the Brief Pain Inventory between treatment groups with 90% power at the 5% level of significance assuming a standard deviation of 2, 22 patients per group are needed.

To further account for possible loss of power due to attrition, 60 patients will be recruited across the two treatment arms.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
11/02/2019
Actual
Date of last participant enrolment
Anticipated
11/02/2022
Actual
Date of last data collection
Anticipated
24/02/2022
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12389 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 12390 0
Monash Medical Centre - Moorabbin campus - East Bentleigh
Recruitment hospital [3] 12391 0
Dandenong Hospital - Dandenong
Recruitment hospital [4] 12392 0
Casey Hospital - Berwick
Recruitment postcode(s) [1] 24655 0
3168 - Clayton
Recruitment postcode(s) [2] 24656 0
3165 - East Bentleigh
Recruitment postcode(s) [3] 24657 0
3175 - Dandenong
Recruitment postcode(s) [4] 24658 0
3806 - Berwick

Funding & Sponsors
Funding source category [1] 301123 0
Hospital
Name [1] 301123 0
Monash Health
Country [1] 301123 0
Australia
Funding source category [2] 301325 0
Hospital
Name [2] 301325 0
The University of Adelaide
Country [2] 301325 0
Australia
Primary sponsor type
Hospital
Name
Monash Health
Address
246 Clayton Road, Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 300823 0
None
Name [1] 300823 0
Address [1] 300823 0
Country [1] 300823 0
Other collaborator category [1] 280455 0
Individual
Name [1] 280455 0
Professor Andrew Somogyi
Address [1] 280455 0
The University of Adelaide, Adelaide SA 5005
Country [1] 280455 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 301875 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 301875 0
Monash Medical Centre
246 Clayton Road,
Clayton VIC 3168
Ethics committee country [1] 301875 0
Australia
Date submitted for ethics approval [1] 301875 0
29/08/2018
Approval date [1] 301875 0
Ethics approval number [1] 301875 0

Summary
Brief summary
This study looks at the effectiveness of a new treatment for cancer therapy-related oropharyngeal mucositis (throat or mouth ulceration) pain.
Who is it for?
You may be eligible for this study if you are aged 18 or over and have cancer treatment-related oropharyngeal mucositis (throat or mouth ulceration) pain.

Study details
This is a randomised controlled research project, meaning that patients will be assigned by chance to either the experimental arm to receive midazolam and ketamine, or to the control arm to receive midazolam alone. This is also a blinded study, meaning that study doctors and patients will not know which group a patient has been assigned to until the end of the study. Participants in both groups will receive medication through a needle in the arm for up to 5 days. All participants will provide blood samples and answer questionnaires.

It is hoped this research will demonstrate ketamine is an effective drug in treating mucositis pain, and this treatment may then be offered to all suitable patients who are also experiencing mucositis pain.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88398 0
A/Prof Peter Poon
Address 88398 0
McCulloch House, Monash Medical Centre
246 Clayton Road, CLAYTON VIC 3168
Country 88398 0
Australia
Phone 88398 0
+61 03 9594 5347
Fax 88398 0
+61 03 9594 5347
Email 88398 0
[email protected]
Contact person for public queries
Name 88399 0
A/Prof Peter Poon
Address 88399 0
McCulloch House, Monash Medical Centre
246 Clayton Road, CLAYTON VIC 3168
Country 88399 0
Australia
Phone 88399 0
+61 03 9594 5347
Fax 88399 0
+61 03 9594 5347
Email 88399 0
[email protected]
Contact person for scientific queries
Name 88400 0
A/Prof Peter Poon
Address 88400 0
McCulloch House, Monash Medical Centre
246 Clayton Road, CLAYTON VIC 3168
Country 88400 0
Australia
Phone 88400 0
+61 03 9594 5347
Fax 88400 0
+61 03 9594 5347
Email 88400 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?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.